NBB 301 Exam 2: Voltage Gated Channels and Action Potentials, NBB 301 Exam 2: Synaptic Transmission, NBB 301 Exam 2: Neurotransmitters and Their Receptors, NBB 301 Exam 2: Postsynaptic Response, NBB 301 Exam 2: Synaptic Plasticity

hebb's postulate

"let us assume that the persistence or repetition of a reverbatory activity tends to induce lasting cellular changes that add to its stability... when an axon of cell A is near enough to excite a cell B and repeatedly or persistently taks part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B is increased" AKA cells that fire together wire together These predictions have been fulfilled by the evidence that LTP is a synapse specific event but that it can occur at weakly firing synapses neighboring high firing synapses Proposed that coordinated activity of a presynaptic terminal and a postsynaptic neuron would strength the synapse between them as is observed for LTP

delay in chemical transmission

1-5ms

properties of LTP (numba one)

1. Pre and post synaptic activity must be coincident. Coincident: needs to happen at the same time (high potential already occurring before stimulus is received) Strong depolarizing pulses and changes in EPSP amplitude happening at the same time. So many strong pulses that they're happening at the same time. When action potentials in a small number of presynaptic Schaffer collaterals that normally produce EPSP are paired with strongly depolarized postsynaptic then the activated Scaffer collateral synapses undergo LTP—these events need to be coincident for this to be the case

NMARS implement rules of LTP

1. Pre and post synaptic activity must be coincident: NMDAR requires presynaptic input and postsynaptic depoarlization 2. LTP is synapse specific: NMDAR only opens at synapses that are releasing glutamate (although depolarization might spread) 3. LTP shows associativity: strong stimulation can depolarize postsynaptic cell and remove Mg block at pathway 2. Associative depolarization provided to relieve the block.

Steps in Chemical Synapse

1. Transmitter is synthesized and then stored in vesicles 2. An action potential invades the presynaptic terminal 3. Depolarization of presynaptic terminal causes opening of voltage-gated Ca channels 4. Influx of Ca through the channels. Rapid because there is a steep concentration gradient present 5. Ca causes vesicles to fuse with presynaptic membrane 6. Transmitter is released into synaptic cleft via exocytosis 7. Transmitter binds to receptor molecules in postsynaptic membrane 8. Opening or closing of postsynaptic channels 9. Postsynaptic current causes excitatory or inhibitory postsynaptic potential that changes the excitability of the postsynaptic cell 10. Removal of neurotransmitter by glial uptake or enzymatic degradation. Removal involves diffusion away from the postsynaptic receptors in combination with reuptake by nerve terminals or surrounding glial cells, degradation by specific enzymes, or combination of these mechanisms

properties of LTP (numba 2)

2. Synapse specific. Happens only on the active (is firing). Inactive doesn't have this effect. No NT is released When LTP is induced by activation in one synapse it does not occur in the other inactive synapses. So it's limited to only active synapses instead of all synapses on a given cell

distance between pre and post in chemical

20-40nm

properties of LTP (Numba 3)

3. LTP shows associativity. If both pathways are active but one has really strong stimulation while the other has weak, there is LTP at pathway 1 and there will be some LTP at pathway 2 but the strong synapse is helping facilitate this So both pathways undergo LTP. Selective enhancement of conjointly activated synapses

distance between pre and post in electrical

3nm

g protein coupled receptors

: also called metabotropic. Called this because the eventual movement of ions through a channel depends on intervening metabolic steps. This includes a receptor molecule that the transmitter binds to and interacts with. In separate molecule you have the channel that ions are going to travel through. They way these two are connected at via the Gprotein cascade. Gprotein bound to receptor; once activated, Gprotein dissociates and typically the alpha subunit binds to an effector protein which then generates an intracellular messenger and then that interacts with the ion channel creating a change in conductance of the ion channel. Can either open or close the channel. Thus, G=proteins are transducers that couple neurotransmitter binding to the regulation

Conventions about ion flow

A membrane current (biological current) that is negative/inward (depolarizes the cell). Ex- sodium current flowing into the cell A membrane current that is positive/outward (hyperpolarizes the cell) Injection current is positive if it is depolarizing the cell Injection current is negative if it is depolarizing the cell

Acetylcholine Degradation

Acetylcholine Degradation Acetylcholinesterase degrades Acetylcholine into acetate and choline in the synaptic cleft. Rapid process because it has very high catalytic activity Highly concentrated in synaptic cleft Rapid and robust degradation 5000ACh/ 1AChE/ sec

Acetylcholine synthesis

Acetylcholine Synthesis Acetyl CoA, from glucose Choline = B complex vitamin. Comes into the cell. Acetyl CoA and Choline (precursors) are turned into Acetylcholine by the action of the choline acetyltransferase (CAT) in the presynaptic terminal CAT for synthesis Vesicular acetylcholine transporter (vACht) used for loading vesicles. Approximately 10,000 are loaded into a single vesicle

Acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors prolong duration of nACh receptor activation

agonists/antagonists

Agonist/ antagonists. Agonists bind to activate and antagonists bind to inactivate can be used to investigate NT

Agonist/Antagonist

Agonist: molecule that binds to the receptor and activates it. All NT are agonists at their receptors. Antagonist: binds to the receptor and does not activate it—prevents other agonists from binding

associative learning

Associative learning: includes both classical and operant conditioning. Emotional musculature invokes the amygdala. Skeletal musculature invokes the cerebellum

expression

Because it's over a longer time scale, NDMAR can only be activated for so long Once calcium goes in, activates a bunch of intracellular pathways that are dependent on calcium. Causes phosphorylation of many substrates. This results in AMPA receptors being inserted on the surface. So now there are many more receptors on the surface. So you'll get elevated response because there is more receptors. This is how the strong response is maintained. Decreased a little because the high frequency stimulation has dropped off. But now you just apply just normal stimulus. Effect is that you recruit more AMPA receptors. Maintenance is attributed to these extra recepts. This increases the postsynaptic response to release of glutamate. Maintained as long as LTP is maintain. Expression is blocked by AMPA receptor antagonists Mediated by Calpain, CAMKII, PKC the calcium activates calmodulin kinase II (CaMKII) and protein kinase C (PKC) which then go on to phosphorylate substrates. eventually results in increased recruitment of AMPA on the cell membrane.

Benzodiazepine and barbiturates

Benzodiazepine and barbiturates are modulators of GABAa allow the channel to remain open longer which results in a longer inhibitory response—these are not required for the channel to work though. Binding sites for bariturates of these is located within the pore of the receptor. Binding site for benzodiazepine is located on the outside of the cell.

Temporal Categories of Memory

Can also think about categorizing based on memory about what time scale they operate on includes short term and long term Immediate memory feeds into working memory feeds into long term memory All components feed into forgetting Descriptions but don't tell us about what is happening in the brain. Synaptic plasticity in the brain plays a big role. Esp turning short turn memories into long term memories

co-transmission

Can be co-transmitted at a single synapse. Many types of neurons synthesize and release two or more different NT. Differential release according to synapse activity. This is because different types of transmitters can be packaged in different populations of synaptic vesicles.

Conductance of voltage gated channels at different membrane potentials

Can do this similar measure for many different step potentials. Can then start to build graphs that involve the conductance for sodium or potassium at certain membrane potentials. What you're actually measuring is your voltage step and resulting current. Using Ohm's law, can derive the conductance of a specific ion. Know the reversal potential is when your applied voltage results in zero current. Know early current is sodium and late is potassium. At very negative potentials (around resting potential), there is practically no conductance for sodium. When you're very depolarized, though, there is a very large conductance for sodium. So these are voltage dependent channels. At rest, there is a nonzero conductance for potassium so the potassium conductance dominants at rest and the resting potential is closer to the potassium reversal potential. Were able to conclude the sodium and potassium conductances change over time because they require some time to activat, especially potassium conductance has a pronounced delay. This more rapid activation of Na allows the Na conductance to reach its maximum more rapidly—more rapid inward current of Na before K current outward. These conductances are also voltage dependent.—both conductances increase progressively as the neuron is depolarized. Both conductances are quite small at negative potentials, maximal at positive potentials.

Channel Kinetics

Channel kinetics determine EPSC shape Individual receptor ion channels don't all have the same open and close times. It's the population of channels that defines the shape of the current trace. Macroscopic current curve is composed of many individual channels opening and closing Graph A: analyzing 6 different channels. Short huff of ACh applied. Most open up immediately and start conducting inward current. And then there is a stochastic pattern of unbinding. Probability of transmitter being bound decays over time. Graph B determines the shape of the EPSC. Graph makes it look instantaneous... it is pretty fast because it doesn't need to diffuse very far, but it is by no means instantaneous. Mathematically, the EPSC is represented Probability of channels being open depends on the ligand concentration. Is zero if there is no ACh around. Kind of a derivative of Ohm's Law (determining conductance is more involved in this situation)

neurotransmitter defining criteria

Chemical released from the presynaptic neuron. Always the case that these have calcium dependent release—more free calcium inside presynaptic terminal leads to eventual release of neurotransmitter Defining criteria of NT: present in presynaptic neuron. Ca dependent release after depolarization. Postsyanptic receptors.

Cadmium effect on postsynaptic membrane potential

Clamping the voltage of the presynaptic cell. Causing depolarization. Then they are measuring the calcium current in the presynaptic cell (down current is calcium coming into cell). When you use drug that blocks calcium channels—the presynaptic calcium current is eliminated. Cadmium is used to block the calcium channels The amount of NT released is very sensitive to the amount of Ca that enters When look at post synaptic membrane—for normal you get post synaptic depolarization Don't get any depolarization in postsynaptic cell when Ca channel blocks Relies heavily on Ca signaling

Co localization

Co localization: small molecules are localed at the pre synaptic end of the cleft and ready to be released (ready releasable pool). Then receptors are often ideally positioned right across the cleft. But the neuropeptide transmitters are released not sitting right there at the presynaptic density but rather released more diffusely. So these are not co localizaed.

Coexpressed

Coexpressed: both types of NT existed both in the same presynaptic

Membrane Potential and resulting current in end plate

Controlling the membrane potential in this case. You apply ACh so that channel can open and you measure the current that is flowing At 0mV, nothing is flowing even if the channel is open. This is because the reversal potential for the receptor is 0mV. At +70mV there is a set outward current. At +50mV you get a smaller outward current. At -50mV and -70mV you get inward negative currents. IV plot. You will find that it's Ohmic as indicated by the linear slope (conductance). Trend is that as the membrane potential increases so does the magnitude of the current flowing. Indicated by gamma instead of g because it is measuring a single channel In real life, a depolarizing inward current is observed

cotransmission

Cotransmission: both types of transmitter in one terminal; sites of docking are different, less number of dense core vesicles Two classes: small molecule and neuropeptides

applying strong tetanic stimulus and measure response

Creates rapid increase in calcium Also rapidly using the vesicles

ACh receptor antagonists and agonists

Curare is the antagonist for nicotinic receptor. This would cause paralysis Atropine is the antagonist for muscarinic. Used to be used to dilate pupils—relaxes eye muscles Nicotine is the agonist for the nicotinic receptor Muscarine is the agonist for the muscarinic receptor

Action Potential (include values like time, magnitude, etc.)

Currency of information in nervous system Action potential is a change in membrane potential from rest to a depolarized value (usually overshooting zero and the cell inside becomes positive). Then drops down below the resting potential and finally arrives back to resting state. Happens on time scale of milliseconds. If stimulus doesn't reach threshold, small passive currents observed. These are failed initiations Rising phase= rapid depolarization. Peak is close to the sodium reversal potential. In AHP you are below resting membrane potential; this is a the refractory period when it is very hard to cause another action potential to happen. All or nothing in that you either have an action potential or you don't; uniform amplitude Amplitude is about 80-100mV from Vrest Width is 1-3 ms in vertebrates

EPSP and IPSP summary

EPSP always depolarize while IPSP can either depolarize or hyperpolarize depending on the situation. An EPSP has a reversal potential more positive than threshold and IPSP has a reversal potential more negative.

pharmocoloy and Na/K voltage gated channels

Early experimenters did not have the same tools available to them If we depolarize native neuron, see normal early inward and late outward. Using neuropharmacology: use TTX (tetrodotoxin). Comes from the puffer fish. This is a blocker of voltage dependent sodium channels. These are not only in neurons but also in heart, so if you inject you're heart stops beating and you die. When applied to neuron, you get almost no inward current (very close to zero) and you're left with mostly an outward current. Now clear that blocking sodium channels block the early component of current—now know that the early inward current can be attributed to sodium ion flow. Tehtraethylammonium: blocks potassium channels. If you use this, you are left with only the early inward current. This is confirmation that there are two distinct mechanisms that create the action potential—evidence that sodium and potassium flow through independent permeability pathways

Chemical Synapses

Electrical synapses are the simplest you can image Chemical are much more common and complex. More ways the chemical synapses can be controlled and modulated Pictured" the axon terminal. Synaptic bouton or presynaptic process. The bottom neuron is the postsynaptic neuron When an action potential comes down axon, triggers events that allow vesicles full of neurotransmitters to fuse with the membrane and spill neurotransmitters into synaptic cleft. Then these bind to receptors on postsynaptic membrane. Triggers electrical activity in the post synaptic cell In chemical synapse, there is always the pre synaptic and post synaptic whereas in electrical this distinction doesn't really exist. There are electrical events involved in chemical synapses but crucial chemical step The action potential does not cross the membrane to the postsynaptic cell Synaptic cleft is about 20-40 nm 1000s of molecules of NT in a signal vesicle?? Vesicles cluster at active zones so they're ready to be released Molecular machinations result in a delay of 1-5ms. Lack in speed is made up for in the amplification of the signal

stabilization

Even more long term Not only increases AMPA receptors but also stabilizes it by having effect on gene transcription. Genes being expressed more are the ones that are causing the neuron to literally grow in size This is the most long term phase. Number and size of synaptic contacts grow during this phase. Make LTP essentially permanent Protein synthesis and mRNA synthesis Genetic transcriptional changes cause this Caused by calcium increase More AMPA too. calcium increase activates calmodulin which then activates protein kinases which then act on G protein to create cAMP which activates protein kinase A to result in changes in transcriptional regulator CREB which turns on teh expression of a number of genes that produce long lasting changes in PKA activity and synapse structure (synapse growth proteins are released)

Acetylcholine

Excitatory NT Utilized in the CNS and neuromuscular junction

Quantal Nature of NT Vesicles

Experiment in low Ca. Values were measured and graphed. Spontaneous was equivalent to the smallest evoked mini. Fixed size because vesicles are released in quantal nature—only ever see the smallest value and then the double, triple, quadruple, etc etc of that. EPP is a smooth graph while this isn't because EPP shows thousands of these being released at once whereas this is looking at the microscopic scale Failure= stimulate but there is no miniature EPP at all. Sometimes little one and sometimes big one. Plotted. Big peak at .4mV and .8mV There is not an infinite number of sizes—discrete units vesicles are causing this distribution. NT can't be released in any amount but rather these discrete units. Y axis: how often we observe that. X axis: magnitude of EPP amplitude. There is trial by trial variability EPP represent the simultaneous release of many MEPP at once. Presynaptic action potential causes a postsynaptic EPP because it synchronizes the release of many transmitter quanta

GABA Synthesis

GABA Synthesis Precursor is glutamate from TCA Glutamic acid decarboxylase (GAD) converts glumate to GABA Vesicular inhibitory amino acid transporter (VIATT) loads vesicles with GABA Localized in the brain Main inhibitory neurotransmitter

GABAa

GABAa allows for chlorine ions to flow into the cell once the GABA has bound to the postsynaptic. This causes hyperpolarization. This is an ionotropic receptor The reversal potential for Cl is usually more negative than the threshold of neuronal firing. So, activation of these receptors causes on influx of chloride that inhibits the cell GABA receptor itself is inhibitory because it is what allows for this chlorine ions to flow into the cell Decrease in firing because it's inhibitory the postsynaptic neuron

GABA Removal

GAT (transporter) removes GABA from synapse. Located on glial cell. Reuptaken with the GAT transporter with is found on the presynaptic terminal and the glial cell—glial cell helps clean up and is also recycled into the cell

summary of electrical and chemical synapses

Gap between electrical is smaller than chemical—chemical needs gap in synaptic cleft for diffusion of neurotransmitters Almost no delay to electrical synapses Chemical—presyanptic and postsynaptic results in flow in only one direction (unidirection) whereas in electrical ions can flow back and forth in either direction

common NT

Glutamate, most common. GABA and Glycine also very common. Also there are dopamine, serotonin, norepinephrine, acetylcholine, neuropeptides, others (ATP, etc) Multiple NT can produce different can produce different types of responses on individual postsynaptic cells

Glutamate Synapse

Glutamate. Typical rest is -60mV. When excited, pulls toward the reversal potential. Most prevelant excitatory synapse is glutamate synapse (80%). This receptor channel also has 0mV reversal potential because ion channel is nonselective to permeable cations. So these are synomious. Open channels to pull voltage upward (depolarized). If strong enough, it crosses threshold for action potential and actio potential is fired.

Glutamate Synthesis

Glutamine is precursor from glial cells, predominantly. Transformed into glutamate using the enzyme glutaminase Packaged by vesicular glutamate transporters (VGLUT) Localized everywhere in the brain Main excitatory NT

glycine removal

Glycine Removal glycine transporter removes glycine from synaspse

glycine synthesis

Glycine Synthesis Serine is precursor. Serine is transformed into glycine by the serine hydroxymethyltransferase Vesicular inhibitory amino acid transporter (VIAAT) loads glycine into vesicles (same thing that GABA uses) Localized in the brain and spinal cord Inhibitory NT

Calcium chelators

Graph C: Involves microinjection of calcium chelators (chemicals that bind to calcium and keep its concentration buffered at low levels). Stimulate the presynaptic terminal in the presence of a buffer for calcium (this prevents or greatly decreases any calcium concentration changes that might happen). If you stimulate the presynaptic terminal now, there is no or very little post synaptic response. It can't increase the concentration of calcium because it gets buffered away—no neurotransmitter release and no post synaptic response. Shows that calcium concentration increase is necessary Calcium is necessary for transmission Prove tat a rise in presynaptic calcium concentration is both necessary and sufficient for neurotransmitter release

HM

HM He had hippocampus resection surgery from his severe epilepsy. Removed some of hippocampus to stop seizures that were originating her Temporally graded retrograde: could remember his childhood. But not recent things. Had no declarative memory beyond 20 seconds but motor learning and spatial memory were intact Anterograde amnesia: couldn't acquire any new long term memories His motor learning was still intact—could learn how to draw shapes well Spatial memory was also still intact Helped us understand that the hippocampus is critical

behavioral habituation and sensitization

Habituation: after stroking a lot, the response becomes less Sensitization: occurs after the shock. More strong response to the stroke now. Habituation: if you just keeps touching it, the response keeps decreasing. Synaptic depression Sensitization: if you shock the tail and then touch the siphon, makes larger response. Pairing siphon touch with electric shock to the tail. This is because it learned it might get shocked again. If you keep doing it, it will slowly habituation again Simplest form of long term memory.. response will elicited for at least an hour

Relating the conductances to the action potential

Hodgkin and Huxley did this. The goal was to determine whether the Na and K conductances alone are sufficient to produce an action potential. Top graph is the membrane potential during an action potential. Using math, you can relate this to the conductances of sodium and potassium at certain potentials. During the upstroke, there is a very fast increase in sodium conductance. These sodium channels were initially closed at the resting potential with zero conductance. With this increased conductance sodium is now able to flow into the cell, causing rapid depolarization. Approaches the reversal potential of sodium. Then in inactivation, the sodium conductance closes back down and the sodium conductance decreases. At the same time, potassium opens during action potential but potassium much more slowly than sodium. This causes K to leave the cell and repolarize the membrane toward the reversal potential of K. Because the K conductance temporarily becomes higher than it is at resting condition, the membrane potential brifly becomes more negative than the normal resting potential, creating the undershoot. The potassium channels don't look to the sodium channels for what to do—these are independent processes but they both are dependent on the membrane potential. The hyperpolization of the membrane potential causes the voltage dependent K conducatnace (and any Na conductance not inactivated) to turn off, allowing the membrane potential to return to its resting level. The relatively slow time course of turning of K conductance as well as the persistence of Na conductance inactivation, is responsible for the refractory period

synaptic plasticity hypothesis

How does this work in the long term though? Different mechanisms used Short Term Forms of Synaptic change include Facilitation, depression, augmentation, post-tetanic potential Act on the ms to sec time frame Influences long term memory. Going from short term to long term is the process of memory consolidation Long term memory acts in the more than a minute time frame. Forms of synaptic changes includes long term potentiation, long term depression. Memory consolidation involves long term stabilization of synaptic changes, due to gene expression, new protein, and morphological changes

Increasing the extracellular calcium levels and EPP

If calcium was slowly increased, the amplitude of the unit synaptic potential doesn't change but the number of failures decrease and the incidence of higher amplitudes increased... so calcium doesn't affect the size of the quantum of transmitter but the average number of quanta released instead

Na and K Movements During EPC and EPP

If membrane potential is 0mV (the reversal potential of the entire channel), you still have sodium flowing in because chemical drive and potassium flowing out because of chemical drive. No electrical drive at this membrane potential. No net current. So no membrane potential change in postsynaptic If you go to -100mV (potassium reversal potential at NMJ). There is no chemical drive for potassium (no potassium flowing out). But you do have big inward current of sodium flowing in causing a big depolarization. At the sodium reversal at the NMJ (+70), there is no net flow of sodium just potassium flowing out. Causes a big hyperpolarization If you stimulate presyanptic and observe what happens to postsynaptic—there is a postsynaptic voltage repsonse (second graph on bottom) depending on the baseline postsynaptic membrane potential Muscles hyperpolarized at rest. Depolarization causes a muscle contraction. When ACh released—postsynaptic depolarized and excited. These graphs, they represent two different experiments. To measure the EPC, you need to use a voltage clamp. Whereas to measure the EPP you need a current clamp. Cannot measure both at the same time because they require different clamps Muscle fiber resting potential is -90mV, so there is only a small driving force on K and a large one on Na. Thus during EPC, much more Na flows into the cell (depolarizing) than K flows out. At the reversal potential of 0mV. The Na and K fluxes are equivalent so no current flows during the opening of ACh channels. EPP vaies in parallel with the amplitude and polarity of EPC. The polarity and magnitude of EPC depend on the electrochemical driving force which in turn determines the polarity and magnitude of EPP Although we have been focusing on the neuromuscular junction, similar mechanisms generate postsynaptic reponses at all chemical synapses. More generally referred to as postsynaptic current (PSC) which in turn changes the postsynaptic potential (PSP). PSP are depolarizingn if their reversal potential is more positive than the postsynaptic membrane potential and are hyperpolarizing if their reversal potetnial is more negative

Patch Clamp: continuous with cytoplasm

If the membrane patch within the pipette is disrupted by briefly applying strong suction, the interior of the pipette becomes continuous with the cell cytoplasm. This allows for measurements of electrical potetnials and currents from the entire cell and is therefore called whole cell recording. Also allows for diffusional exchange between the solution in the pipette and the cytoplasm which allows for a convenient way to inject substances into it

depolarizing up to zero in voltage clamp experiment

If you instead depolarize up to zero, there is a quick capacitive current when you quickly charge up the capacitor but then there is a brief inward current (less than 1ms) and then a delayed outward current that continuous as long as you keep the depolarization going. The fact that these things following the capacitive current conforms that the membrane permeability of axons is indeed voltage dependent

summary of LTP in NMDAR

In summary, Ca enters through postsynaptic NMDA receptors which leads to activation of protein kinases that regulate the trafficking of AMPA receptors, thereby enhancing the postsynaptic response to glutamate. The longer lasting changes rely on changes in gene expression

The Influence of the Postsynaptic Membrane Potential on End Plate Currents. resting potential. manipulating by blocking certian ions from flowing

Includes many channels on the plate As we change postsynaptic membrane potential, we can measure the postsyanptic current amplitude to create another IV curve. Use a voltage clamp to control the end plate potential Reversal potential is zero and no net current is detected flowing at this value. Even though when the channel is open it is pretty much equivalently permeable to K and Na, the resting membrane potential is primarily generated by Na influx. EPC= end plate current. Because it's just a population of the same underlying channels, find a similar Ohmic IV curve. Conductance is the conductance of the whole neuromuscular junction Looking where it crosses the horizontal axis (at what membrane potential is the current zero aka the reversal potential of the entire plate) Can manipulate neuromuscular junction by using drugs to block other channels so that only one type of ion channel is open. These all have the same slope but the line will just shift. These are the reversal potentials of the single ion Neuromuscular is not just conducting on type of ion because it doesn't match any ion reversal potential The EPC is large and inward at large negative potentials but becomes smaller in magnitude as the membrane potential approaches zero

voltage clamp method

Initially done in the squid giant axon. Squish out cytoplasm and control the membrane as you wish. Diameter is close to 1mm. 1. One internal electrode measures membrane potential (Vm) and is connected to the voltage clamp amplifier 2. Voltage clamp amplifier compares the membrane potential to the desired (command) potential 3. When Vm is different from the command potential, the clamp amplifer injects current into the axon through a second electrode. This feedback arrangement causes the membrane potential to become the same as the command potential. 4. The current flowing back into the axon, and thus across its membrane, can be measured her. This allows you to completely control the membrane potential across the membrane of this axon Whatever you are injecting is the same as the current flowing across the membrane. Called the voltage clamp because it controls or clamps the membrane potential at any lvel desired by the experimenter The membrane potential is held at the desired level even in the face of permeability changes that would normally alter the membrane potential Voltage clamp technique can indicate how membrane potential influences ionic current flow across the membrane Command voltage is the desired voltage Now the voltage is controlled (independent variable). Current is measured (dependent variable). Current it takes to maintain a certain voltage is measured. This is useful because it allows you to determine how different potential different affect the rate of current flow. Allowed scientists to measure different permeability changes with changing membrane potential

injecting calcium into presynaptic when presynaptic potential is not modified

Inject calcium into presynaptic terminal artificially and look at post synaptic response. The post synaptic terminal depolarizes. Nothing is done to presynaptic potential—only calcium is injected. Thus, calcium triggers a release in neurotransmitters even in the absence of an action potential. Shows that calcium concentration increase is sufficient

Protein synthesis is necessary for...

Intra-cerebral infusions of puromycin (a protein synthesis inhibitor) 5 hours prior to tY maze training do not disrupt retention tested 15 after training but does disrupt retention tested at 45 minutes or 3 hours after training Mouse model: testing how his long term memory works Maze: get shocked in different areas of a maze when the mouse is exploring. To test if it is really long term regulatory that is causing these changes, increase the protein synthesis blocker. Can still use all short term mechanisms. Train in the maze. If you put back into maze after minutes, remembers If you take out for 45minutes, doesn't do great. This exceeds the amount of time that the short term mechanisms can be effective This shows us that protein synthesis is really important for the consolidation of memory whereas it is not so important for short term memory

Chemical signaling at NMJ

Ionotropic Ach at the neuromuscular junction (synapse between the nerve cell and the muscle). The receptor channel responsible to the response of the muscle is ACh channel ACh receptors are located on the muscle fiber membrane When there's no ACh bound, this channel is closed. When two molecules are bound, the channel is opened. Small molecule NT NT is released via Ca mediated vesicle fusion in response to a AP reaching the synaptic terminal of the neuron. ACh in cleft binds to receptors, which directly opens ion channels allowing specific ions to flow into the postsynaptic cell. This current causes a postsynaptic voltage response. Electrical to chemical to new electrical signal

GABA

Ions: Cl. Erev= -70mV. Receptor: GABAa. Action: IPSC

Glutamate (non-NMDA)

Ions: Na/K. Erev= 0mV. Receptor: Non-NMDA (AMPA/Kainate). Action: EPSC

Acetylcholine

Ions: Na/K. Erev=0. Receptor: nicotinic AChR. Action: EPSC

Glutamate (NMDA)

Ions: Na/K/Ca. Erev: 0mV. Receptor: NMDA. Action: EPSC and Ca

LTP is accompanied by

LTP Accompanied by Increase Synapse Size and Local Protein Synthesis When you have increased protein synthesis, have increased synapse size. Neuron size can be maintained over long period of times—increasing the size and strength of neurons is something that can be maintained over many years Synapse size: more room for more AMPA receptors Size of neuron itself is bigger, so you have a lot more room for receptors itself. Increase in AMPA receptors. So by increasing the size of the neuron you have a long term ability to increase these AMPA receptor amount Calcium dynamics in the system also change—more space and ability to be excited seen with 3D serial reconstruction using electron microscopy Alterations in calcium dynamics and room for more AMPA receptrs

LTP phases

LTP Can be Divided into Three Phrases Induction phase: stimulation is happening so sharp increase in the EPSP Expression: "early LTP." increase in amplitude is maintained but goes down a little Stabilization: "late LTP." goes down more. Is stabilized Stable for many hours, days, weeks

long term potentiation and the rodent

LTP creates acitivty that produces a long lasting increase in synaptic strength Rodent brain Serial and parallel pathways in hippocampus Apply stimulus to synapses of CA3 on CA1—found you could enhance efficiency at synapse (same input could elicit greater response) When high frequency stimulus given: postsynaptic potential increase increases only in pathway one If it has the properties of LTP, then LTP will be observed Increases in activity at a synapse enhance efficiency of communication at that synapse Tetanus= very strong stimulation leading to lots of activity Is LTP the physiological correlate of learning and memory? CA3 pyramidal neurons send action potentials down their axons (Schaffer collaterals), that synapse onto CA1 pyramidal neurons Electrical simulation of Schaffer collaterals generates EPSP in CA1 cells. If the Schaffer collaterals are only evoked a few times per minute, the size of EPSP in CA1 remains constant. However, a brief, high frequency train of stimuli to the same axons causes LTP. The long duration of LTP shows that this form of synaptic plasticity is capable of serving as a mechanism for long lasting storage of information This is primed to be the mexhanism by which the brain learns and stores memories—activation of pathways that induce long changes in that pathway

long term memory

Long term involves more than a minute time frame. Includes long term memory (days to years) and kinda of working memory (seconds to minutes). Involves changes in synapses

Nicotinic ACh Receptor

Many of the postsynaptic actions of ACh are mediated by the nicotinic ACh receptor (nAChR). Ligand gated channel, Ionotropic nAChR are nonselective cation channels that generate excitatory postsynaptic responses. Width of the pore is large enough that it doesn't discriminate Named after the kind of agonist that activates them (nicotine) 1 subunit with 4 transmembrane domains (M1-M4) Allows for the movement of sodium into the cell. 5 subunits form cation selective channel Two molecules of ACh required for gating the channel. So only relatively high concentrations of ACh can activate these channels. This ion channel is selective for cations—M2 region is responsible for this because it has negatively charged amino acids lining its pores so it attracts the positive cations. M2 transmembrane domain has negatively charged amino acids lining its pore—responsible for cation specificity Binding of ACh causes a conformation change that rearranges the receptor transmembrane domains, therefore opening the gate and permiting ions to diffuse through the channel pore This general arrangement of several receptor subunits coming together to form a ligand gated ion channel is characteristic of all the ionotropic receptors

short term synaptic depression

Many stimulation applied for long period of time When you do this, you can get depression Hypothesis is that even though you have this huge influx in calcium, you still need to bring the vesicles back and recycle. Can't keep up. Becomes depressed Time scale seconds Referred to as the vesicle depletion hypothesis Synaptic depression causes NT release to decline during sustained synaptic activity Depression depends on the amount of NT that has been release. Lowering the extracellular calcium which reduces the quanta of Ca released, can slow the rate of depression Depression is caused by progressive depletion of a pool of synaptic vesicles that are available for release: when rates of release are high, these vesicles deplete rapidly and cause a lot of depression; depletion slows as the rate of release is reduced, yielding less depression. According to this, depression causes the strength of transmission to decline until this pool is replenished by mobilization of vesicles from a reserve pool Correlation with strength of input signal to output signal and all dependent on the number of reusable vesicles

Aplysia Ink Jet Response

Marine animal Evoke this behavior by poking them in the tail Use a combination of electrical and chemical synapses Sensory neuron responds to stimulus. Makes synapse onto premotor neuron—the motor ones are gap junctioned to each other so change in membrane potential in one of these neurons will affect the rest. These have big neuorns When you touch tail of the animal they all have roughly the same activatation at the same time—pretty instantaneous. Allows for the ink jet response When you hyperpolarize it, the ink release is inhibited because action potentials not created Electrical synapse so the membrane potential changes are observed essentially simultaneously at all the different neurons

location of synapses

Matters. Typically think about inputs coming in on the dendrite. Example on right. Two synapses onto the same postsynaptic neuron. If cell A if active, at V2 locally, fairly big postsynaptic potential. But once it travels down to dendrite and decays, at V1 there is a much smaller signal. If call B is active, at V1 locally there is a large current. And V2 there is smaller from back propagation. In terms of influencing the membrane potential at the trigger zone, cell B has more say. Cell A input experiences a lot of decay by the time it reaches the trigger zone. This is how an inhibitory synapse near the trigger zone can veto an action potential more easily So location does impact a synapses ability to contribute to affecting an action potential

action potential mechanism summary

Membrane potential need to reach a specific threshold (due to excitatory synaptic inputs onto the cell) for action potential to occur. This is when the sodium current is great than the leak current. Rising phase: occurs due to rapid increase in sodium conductance At the peak, the membrane potential is near the reversal potential of sodium At this point, there is sodium conductance inactivation and the activation of potassium begins. Repolarization: the current of potassium is much greater than sodium. This brings the membrane potential back down Creates hyperpolarization because potassium channels are also slow to close. Brings membrane potential closer to the reversal of potassium.

induction

Mg block on the NMDAR is removed. So it is opened up and calcium is allowed to flow through. It then acts as a second messenger to induce LTP through a signaling cascade LTP induction thus can be blocked by NMDA antagonists and calcium buffers injected into the post synaptic cell

Modulation of GABAa

Modulation: sightly modified the way a receptor works. These are not naturally present, usually brought in by drugs. Adjust or change the function. Here it adjusts how long the channel it opens. But doesn't allows have to be this effect—depends on how it interacts with the other amino acids in this pore This is not the only postsynaptic receptor for GABA: also has GABAa, GABAb, and GABAc

molecular mechanisms that underlie sensitization

Molecular Mechanisms Molecular mechanisms that underlie sensitization (about one hour lasting): g-protein coupled receptor (GPCR) activated by serotonin receptor that is released by facilitatory interneuron → adenylyl cyclase --> cAMP → PKA → phosphorylates K channel, etc Prolongs the action potential by reducing the probability that the K ion channel will be open. potential thereby opening more presynaptic Ca channels. Increases the amount of NT released onto the postsynaptic Does not require gene expression and protein synthesis Long term sensitization (days) similar beginning to process. persistent PKA. phosphorylates and activates the transcriptional activator for CREB (increases rate of transcription of downstream genes). creates ubiquitin hydrolase that stimulates the regulation of PKA so it no longer needs to be activated by serotonin This only happens with repeated training (more shocks) and lasts for days Requires gene expression and protein synthesis changes Addition of synaptic terminals Different mechanistically although the behavior was the same. Overall, synaptic plasticity can lead to changes in circuit function and ultimately behavioral plasticity

types of NT receptors

Molecules diffuse across the cleft and bind NT receptors are proteins that are embedded in the plasma membrane of postsynaptic cells and have extracellular NT binding sites that detect the presence of NT in the synaptic cleft There are two broad families of receptor proteins that differ in their mechanism of tranducing transmitter binding into postsynaptic responses ligand gated ion channels and g protein coupled receptors Ionotropic tend to elicit quicker responses whereas the signal transduction that must be done tends to elicit slower responses in metabotropic

GABA

Most inhibitory synapses in the brain or spinal cord use either GABA or glycine as NT

NMDA

NMDA is special because of the magnesium block. Goes away with depolarization That's why NMDA also called coincident detector—need both the glutamate and the depolarization NMDAR does instantiates the 3 characteristics of LTP Makes sense why it is only activation during high frequency transmissions. It is blocked by Mg at low frequencies, but the summation of EPSP seen during high frequency creates a prolonged depolarization that expels Mg from the NMDA channel pore This allows Ca to enter the pore and the LTP effects to be had

NMJ vs. CNS

NMJ Not typical but used for historical purposes (one of the first that was studied because of its accessibility and it also operates under extreme circumstances). The fundamental mechanics can be applied to other situations though. There are many differences between NMJ and CNS though. NMJ neurotransmitter is ACh Very reliable 1:1 action potential ratio in the NMJ. CNS inputs needed to be summed up first NMJ vs. CNS ratio of neuronal terminal: NMJ has 1 motor neuron/ muscle fiber CNS has 100s of neuronal terminals/postsynaptic cell NMJ vs. CNS input types NMJ has excitatory input only CNS has excitatory and inhibitory inputs NMJ vs. CNS receptors NMJ has one NT/ one NT receptor CNS has a variety of NTs and NT receptors NMJ vs. CNS action potentials NMJ has 1 action potential in motor neuron = 1 action potential in muscle fiber CNS has 50-100 presynaptic inputs that create 1 action potential in the postsynaptic cell

NMDA channels

Needs glutamate to open channel Glycine is a required cofactor Na and K and Ca ions can flow (gamma is 50pS). Higher conductance than non-NMDA Mg block keeps channel closed at hyperpolarized potentials Gating needs ligand and depolarization. Current from the non-NMDA receptors is needed in order for the postsynaptic cell to be depolarized enough for NMDA receptors to open Needs to be highly depolarized to open Open after the non-NMDA. If these didn't open first, it would be difficult for the membrane to reach this depolarized value for NMDA to be activated. Much higher conductance Longer to open up but cause greater depolarization once they are Magnesium block does not allow ions to flow through until the proper depolarization is reached. It's just around and by diffusion comes into bind and block. Depolarization pushes the magnesium out of its blocking position Coincidence detector means that this will only happen if two things happen at the same time—detects this coincidence If it's open, all three types of ions will be able to flow through EPSCs produced by NMDA receptors are slower and last longer than those produced by AMPA receptors

Postsynaptic Propagation

Neurons are not spherical—need to think about what happens about there is depolarization in the postsynaptic cell Previously we talked about a passive cable that had no voltage gated ion channels. If you inject current in one spot in a passive cable, will flow along the cable and at every point some current will continue to flow while others will flow through the leak channel. Creates an exponential decay that can be described by the length constant. In a dendrite, there is not a lot of voltage gated ion channels. Basically a passive wire. Follows rules of length constant as it propagates. (Decreases to 37% of its original value after a certain length constant). When depolarized, local depolarization. This doesn't locally reach threshold for action potential, so not generated right there when input comes in. So it basically decays as it travels just like a passive cable. Quite a bit smaller once it reaches the cell body. Action potential also not triggered. This is because if you only have a few voltage gated channels, the sodium flowing in only creates slight depolarization. When this slight depolarization felt in presence of many voltage gated sodium channels, the positive feedback loop can begin and cause larger depolarization to create action potential. Keeps decreasing and amplitude in the soma... when it reaches the axon hillock (trigger zone) where the membrane is different than the membrane previously encountered. Has many more voltage gated ion channels. So only needs a little bit of depolarization to create an action potential (it is pretty close to resting membrane potential at this point). From here, can propagate down the axon. Graph is messed up because.... It will go below the resting membrane potential but only after the action potential has passed. This is a spatial diagram at a specific time point. So why would ahead of the trigger zone be hyperpolarized. It wouldn't because hasn't seen any signal coming in yet. What is really should look like it the action potential linen dropping just to the resting membrane potential and not below. Action potential is like a wave, much more spread out than you would think. That's why you can all these different events at different areas in the cell simultaneously at a single point in time, allowing you to make this spatial graph.

neuropeptide

Neuropeptide: smaller class of protein neurotransmitters that have very different properties. Dense core vesicles because they appear electron dense in images. Made by the cell body. Neurons can have incredibly long axons; huge distances between cell body and where it is released. Made in soma and move to terminal by fast transport mechanisms. Up to 400mm/day on them microtubule tracks. DCV membranes are used only once. These are synthesized at cell body and shipped along the axon via fast axonal transport There is not recycling here. There is no recycling at synapse but must be somewhere else or would run out of membrane

Saltatory Action Potential Conduction

Nodes of Ranvier—if the entire surface of the axon were insulated, there would be no place for current to flow out of the axon, and action potentials could not be generated Opening where the axon is bare and not inshealthed in myelin Myelin sheaths wrap the axons but there are gaps High density of voltage dependent ion channels in these areas At these nodes, there is a high density of sodium and potassium channels An action potential generated at one node of Ranvier elicits current that flows passively within the myelinated segment until the next node is reached. This local current flow then generates an action potential in the neighboring segment, and the cycle is repeated along the length of the axon This type of propagation is called salutatory, meaning that the action potential jumps from node to node At point A, call for an action potential. With the myelin sheath, the passive current flows longer distance than before because less leaking (almost no loss) thanks to insulation At point B, the depolarization here causes the action potential to regenerate Faster than without myelin sheath because there's less loss of current flowing out of cable because there are not many myelin channels underneath sheath and the sheath is insulating. By acting as an insulator, myelin greatly speeds up action potential conduction. Called saltatory (jumping) conduction. Action potential seems to be jumping between the nodes Pretty much all current at one node can help depolarize the next node

nonassociative learning

Nonassociative learning: includes but habituation and sensitization. Invokes reflex pathways.

inside out patch clamp method

Other methods. Once a tight seal has formed between the membrane and the glass pipette, small pieces of the membrane can be pulled away from the cell without disrupting the seal; this yields a preparation that is free of the complications imposed by the rest of the cell. By retracting a pipette that is in the cell attached configuration causes a small vesicle of membrane to remain attached to the pipette. By exposing the tip of the pipette to the air, the vesicle opens to yield a small patch of membrane with its former intracellular surface exposed (inside out patch recording configuration). Makes it possible to change the medium to which the intracellular surface of the membrane is exposed.

Patch clamp measurements: K Channels

Patch clamp measurements of ionic currents flowing through single K channels in squid giant axon Force membrane potential with experimentally apparatus to change from -100 to 50mV Measure microscopic potassium current. Find current through little patch of membrane. See that when before you make step there is no current flowing and when you make step current eventually starts flowing but starts at different times. Also can be unpredictably interrupted. Seizes when voltage steps back down. Current is set level when it is coursing though. Stereotyped value. The current of 1pA nonetheless reflects the flow of thousands of ions per millisecond flowing through—a single channel can let many ions pass through the membrane in a very short time Opens when you depolarize membrane but stochastic manner— probability to act in a certain way but you cannot say when a particular channel will act in a certain way. Probability of opening increases with depolarization—doesn't mean that all the channels open at the same time though. Can never tell exactly when it is going to happen If you look at individual neuron—there are thousands of ion channels. When you have huge population of ion channels you cannot predict what each individual one will do at a given time but there is an average pattern that can be observed for the whole neuron You can tell that you're measuring just one channel because some of the recordings of the patch will have really steep steps up—there are two levels of peaks besides zero current. Number of channels correlates to the number of channels present. In graph B. If you average current for single channel after doing experiment many times, can plot the average like graph c. When looking at bigger patch of membrane, you will get a smooth curve like in graph d. Macroscopic level. Even though every individual channel is behaving randomly Probability of membrane channel to be open given a certain membrane potential. Get a sigmoidal curve like in graph E. Current for potassium is positive because positive ions flowing out of the cell

Activation of ACh Receptors

Patch clamp method used Suck onto the postsynaptic muscle cell and rip out a patch of it. Outside out method used which allows you to see how extracellular components influence the channel. Includes just one receptor channel. Can study how it reponds to signals in isolation. Outside out—what was previously on the outside of the muscle cell is now on the outside of patch—would normally receive the neurotransmitter Artifically apply ACh and measure the current through the signal channel. As current flows through this signal channel, two levels of current are observed. Either conducting or not conducting a select value and nothing in between. Opens and closes stocastically (binds and unbinds). With several open channels, it does the same thing but each channel opens and closes independently on their own. As soon as you apply, each independent channel is likely to increase. Then probably decreases as it unbinds and goes away A lot of channels makes this a neat, smooth curve but it is still composed of microscopic tiny steps The electrical actions of ACh are greatly multiplied when an action potential in a presynaptic motor neuron causes the release of millions of molecules of ACh into the synaptic cleft. Then the transmitter molecules bind to the thousands of ACh receptors packed in a dense array on the postsynaptic membrane. Although individual ACh channels only open briefly, the opening of a large number of channels is synchronized by the brief duration during which ACh is secreted from presynaptic terminals. The macroscopic current resulting from the summed opening of many ion channels is called the end plate current. Tends to be inward and cause a depolarization. This depolarizing change in potential is called the EPP which then triggers postsynaptic action potential. This current causes a postsynaptic potential change (PSP). In this cause it is EPSP because it is excitatory. Called EPP here (end plate potential). Current: influx of positive charges into the cell causes a negative current. This causes a postsynaptic depolarization. Reliable. This is a big response. In most causes it will cause an action potental in the posynaptic causing a muscle contraction. Reponse to single cell is usually small so you need many of them doing it together to get an action potential

potassium channel physiology

Potassium channel: has positive charges inside protein. When hyperpolarized, these charges are attracted inside to close the pore. When depolarized, the initially it is still closed because the potassium channel is slow to respond. Finally, the positive charges are attracted to the outside, as they do so they bend the whole protein into a shape that then opens up the pore. When voltage steps back down, the positive charges move in again and bend the whole protein back into a shape that closes channel back up. Evolved this way because efficient way to do this.

priming

Priming: invokes the neocortex

procedural

Procedural: includes skills and habits. Invokes the striatum

But memories last years and the proteins and lipids that comprise neurons are turned over much faster

Proteins and neurons are constantly being turned over So if the whole system just gets replaced, how do we keep these long term memories?

to prove a chemical is a NT

Put on the post synaptic cell. If this creates the same result that the presynaptic cell then it is. Adding NT externally mimics postsynaptic effect

hippocampus

Really critical to different types of memory processing. Involved in explicit memory—important for the formation and retrieval of

events from NT release to excitation/ inhibition

Receptor binding can either directly or indirectly open or close the ion channels (ionotropic or metatropic) Because of this, inhibition is a large shaper of action potential The steps: NT release, receptor binding, ion channels open or close, conductance change causes current flow, postsynaptic potential changes, postsynaptic cells excited or inhibited, summation determines whether or not an action potential occurs

EPP in Absence of Presynaptic Stimulation

Recording membrane potential of the postsynaptic cell Without stimulation from the presynaptic neuron, there is miniature end plate potentials—these happen spontaneously without action potential. Small but have same shape as that on last slide. Same shape as EPPs, just smaller (about .5mV). Sensitive to drugs that block EPPs. Decays with distance. Requires repsynaptic terminal and thus the NT ACh and AChRs. Why? In normal, release of a lot neurotransmitters. Each MEPP (mini end plate potential). is typically caused by single vesicle that is released full of ACh. This discovery lead to discovery of NT. This represents that small amounts of NT are continuously released by the presynaptic terminal (quanta)

Glutamate Removal

Reuptake from the synaptic cleft via excitatory amino acid transporters (EAAT). These are present in glial cells. In the glial cell it is converted back into glutamine.

Local Recycling of Synaptic Vesicles

Right before AP—many vesicles ready for release. Triggered by increase in Ca. Leads to exocytosis. Vesicle fused to membrane. Budding causes a little bit of membrane broken off to recreate vesicles So a bout of exocytosis can increase the surface area of presynaptic terminals, but this extra membrane is removed within a few minutes. Recycled in process called the synaptic vesicle cycle. clathrin surrounds the budding vesicle After they are reformed, they are stored in a reserve pool within the cytoplasm until they need to participate again inNT release Local recycling is well suited because it vesicles were created in the soma and then had to be transported all the way down to the terminal, this would not occur quickly enough to keep up with neuronal activity Only happens with small vesicle Use cytoplasmic enzymes in the nerve terminal

Patch clamp measurements of ionic currents: Na channels

Same idea, different channels First: the microscopic current is negative instead of positive. This is because Na current is inward. Second: Most of the steps in microscopic currents occur earlier after the time that the membrane potential changes. Takes closer to 1ms rather than closer to 10ms for K Third: potassium currents continue as long as the membrane is depolarized. Sodium is inactivating ion channel:: opens quickly but will close despite the membrane remaining depolarized. Transient current: comes on and then switches off. Similar curve in probability of opening when compared to potassium. It is less likely to be open when approaching values for the resting potential, though. Shows that the opening and closing of the channels are voltage depenedent In summary, the patch clamping has allowed direct observation of microscopic ionic currents flowing through single ion channels, confirming that voltage sensitive Na and K channels are responsible for the macroscopic conductances and currents that underlie the action potential

measuring the potential results for alpysia

Same sensory information creates different response: shows evidence of learning. A way of "forgetting" Sensory neuron action potential amplitude is the same. Motor neuron EPSP response varies. Habituation caused by synaptic depression (decreased amount of vesicles available). Creates situation when you have the same sensory input by different motor output observed Sensitization involves an additional modulatory synapse that modulate the synaptic transmission in the gill withdrawal ciruict evidence that learning and plasticity is evident on the synapse level

hippocampus across species

Seen across many species so can use many different species as model organisms

Separating out the post synaptic current for glutamate receptors

Separate out the currents by using specific antagonists for each type of glutamate channel Current traces were recorded at +50mV so that the Mg block was removed NMDAR: agonist is NMDA. Antagonist is APV AMPA/Kainate: agonist is AMPA/kainate and antagonist is CNQX Using antagonist in NMDA in NMDAR: it stops the second part of the depolarization. Only the first initial peak of current is observed Block AMPA receptors: blocks the early current but the second part is still observed. There are few NMDA than AMPA in this example—even though individual channel of NMDA has higher conductance because there are fewer it has a smaller amplitude

different forms of short term plasticity

Short term facilitation Short term synaptic depression Post-tetanic potentiation Different forms of short term plasticity interact in complex ways on msec, sec, and minute time frames

short term memory

Short term involves the ms to sex time frame. Includes immediate memory (fractions of a second to a second). Immediate is housed in each sensory modality. and kind of working memory (seconds to minutes) is short term. Can be used to achieve a behavioral goal

learning and memory in aplysia

Simple forms of learning were identified in the Aplysia by analyzing the behavior of the gill-withdrawal reflex—habituation, sensitization, classical conditioning Major contribution of Dr. Kandel was to utilize this simple system to demonstrate that changes in synaptic strength were at the core of learned behavior Good model organism because neuronal organization is simple and neurons are large so synaptic connections are easily identified Measuring the withdraw response after stroking Gill withdraw reflex Did siphon stroke and tail shock—contractions observed Sensitization: more powerful withdraw for siphon stroke in the animal that has already been tail shocked. This is the process that allows an animal to generalize an aversive response elicited by a noxious stimulus to a variety of other, non-noxious stimuli. Even after a single stimulus to the tail, the gill withdrawal reflex remains enhanced for at least an hour Memory of event Short term memory for one shock, long term memory is shocked multiple times Important: changes at synapses is what caused the learned behavior Synaptic changes are similar from aplysial to mammals and even some of the proteins used in the process are the same—highly conserved Long term potentiation involved in learning and memory because of their lasting duration

general statement about the Na/K channels

Single channel studies show that there are at least two types of channels: one selectively permeable to Na and a second selectively permeable to K. this ion selectivity means that these channels are able to discriminate between Na and K. Because their opening is influenced by membrane potential, both channel types are voltage gated. So each type of channel must have a voltage sensor that detects the potential across the membrane

post tetanic potentiation

Slightly longer short term plasticity: seconds to minutes time scale Hypothesized mechanism: increased calcium causes activation of intracellular calcium dependent kinase causes phosphorylation of synapsin (this protein usually prevents the vesicle from moving from the reserve pool to releasable pool, so modulating it allows synapsin to be more releasable) Increase time scale to minutes Limiting factor usually is the limit of vesicles. So it becomes depressed as it becomes depressed. During this longer break, it has enough time to recover. So you see post-tetanic potentiation later on At first you're facilitating by increasing calcium. Then decreases when runs out of vesicles. Ca recruited more vesicles though, so with the post tetanic is a lot bigger than the initial one. Even if you don't have as much calcium in their, you have much more vesicles and NT to be released in the active zone instead of the reserve pool Depression creates the signal that you need more vesicles There is a short term facilitation followed by short term depression followed by the post tetanic potentiation Potentiation serves to increase the amount of transmitter released from presynaptic terminals. Enhances the ability of incoming calcium ions to trigger fusion of synaptic vesicles with the plasma membrane Arises from prolonged periods of elevated presynaptic calcium levels during synaptic activity Causes chemical synapses to change dynamically as a consequence of recent history of synaptic history `

small molecules

Small molecules are most of what we will talk about. Small clear vesicles (little white ball); you can tell just by looking at microscope image. Different production. These can be synthesized by enzyme. Enzyme created in cell body and then sent near synapse and then creates the NT here. Packaged into vesicles via transporters. Small vesicle (SV) membranes are recycled. Specific transport proteins remove most of small molecules from the synaptic cleft, ultimately delivering them back to presynaptic terminal for reuse Enzymes used to synthesize the NT are made in cell body and then transported to the terminal using slow axonal transport Enzymes change precursor into a NT Vesicle binds to membrane to release NT into the synaptic cleft Usually, some other chemical will degrade this NT and it gets recycled back into the cell. Specific transport proteins remove most of small molecules from the synaptic cleft, ultimately delivering them back to presynaptic terminal for reuse The cell membrane used to enclose NT are also recycled—another process to grab from cell membrane and refill with NT. Called the synaptic vesicle cycle.

Presynaptic potential and calcium

Sodium and Potassium channels blocked—shows that it is all mediated by calcium More depolarize the presynaptic cell- the largest the calcium entry into the cell. Creates different sizes of post synaptic depolarization Systematic changes The more that the presynaptic membrane is depolarized, the greater the calcium current that is induced and the greater the postsynaptic potential

sodium channel structure

Sodium channel: has just one voltage gate. Has positively charged parts—protein is chain of amino acids and some of which have net positive charges. Just as in potassium, has the charges to open and close the pore. It also has an inactivation gate. Start off with pore closed and door open (but current can't flow because pore is closed). Sodium channel is fast to respond to the depolarization; as soon as step is made in the membrane potential, the Sodium pore opens up. But the door is slow so it remains open. Now you have temporary state when ions can flow into the cell, causing upstroke of action potential. Now the trap door (which operates on relatively same time scale as potassium channel) slams shut (inactivation). This is why current comes on when you make a voltage step, but it is brief and does not stay on. When the voltage steps back down, the pore is fast and it closes but the trap door is closed still because it's slower. Then the trap door arrives at open state. No current flowing.

Injecting Current near a Electrical Synapse

Some current will leak out Some will depolarize and repolarize on presynaptic Some will flow onto the postsynaptic cell... so the post synaptic cell will also get depolarized but to a lesser extent. Only so much makes it into this cell because some leaks out Echo of response: smaller in amplitude and slightly slower (but really pretty much instantaneous)

spatial summation

Spatial summation: different locations of transmission into the dendritic tree and almost the same time. Two synaptic currents. With short length constant, the depolarizations created two not travel very far. So you get small blips from each of them because only a little of each make it to the cell body. With a long length constant, the EPSP will travel very far with little EPSP. Allows more to make it to the cell body so they can add on top of one another. Consequences on postsynaptic signaling (action potential or not).

Hyperpolarizing in the voltage clamp experiment

Squid giant axon. Took from resting state and hyperpolarized. A brief capacitive current is observed; this occurs because when you make this rapid change in voltage, you get massive current flowing onto the membrane and charges it but then stops (less than millisecond). Aside from this very brief event, very little current flows when its potential is changed to hyperpolarization

strychnine

Strychnine is an antagonist of glycine. This would cause action potentials to be continuously triggered so there are just muscle spasms

summation of postsynaptic potentials

Summation occurs at the postsynaptic area in the dendrite If the first and second get activated, you get EPSP Usually, activation of one synapse in the CNS is not enough to bring the potential to threshold as opposed to in the neuromuscular junction where just one input is enough to reach threshold. When all three together in this example, you can't reach threshold An average, a neuron has thousands to tens of thousands of synapses. Sees a mirage of this and they get summed up—complex fluxuation of membrane potential and occasionally reach threshold. When threshold is not reached: not a pure EPSP or pure IPSP—refer to it as a depolarization Summation thus allows subthreshold EPSPs to influence action potential production Summation of EPSPs and IPSPs by a postsynaptic neuron permits a neuron to integrate the electrical information provided by all inhibitory and excitatory synapses acting on it at any moment. Whether the sum creates an action potential or not depends on the balance between excitatory and inhibitory. Normally, this sum is continually changing over time. NT induced tug of war

Where are synapses found?

Synapse between axon and dendrite is really common but there are other types Axocomatic: axon synapses on the soma Axodendritic: normal Axo-axonic: axon synapses onto another axon Swollen presyanptic processes in these En passant: two axons touching each other in passing and don't form swollen presynaptic density but can still have activity

neuromuscular junction

Synapse between axon and muscle fiber. They are simple, large and peripherally located Much of the evidence leading to our present understanding of chemical synaptic transmission was obtained from experiments examining the release of ACh at neuromuscular junctions Way that the brain controls the body is through the neuromuscular junction—translates brain activity into action In spinal cord Nerve tells muscle to contract through chemical transmission Endplate: input from single axon. Postsynaptic potential at only neuromuscular junction Can electrically stimulate axon. Trigger potential in muscle cells (these are electrically excitable just like neurons). Called the end plate potential (EPP) when it is depolarized in this way. Action potential fires in the muscle when the EPP exceeds threshold. This causes the muscle fiber to contract. EPP caused by the end plate current. Usually causes a depolarization because of the inward current Neuromuscular junction: most neurons in the brain gets input from 25 others on average. These are usually pretty weak—just one input usually isn't enough to make postsynaptic cell to fire. Muscles cells only get input from one. This is super sensitive—a single action potential is enough to bring the muscle cells potential up to threshold. Every time there is action potential in presynaptic there is one in post synaptic So, overall: one action potential presysnaptically depolarizes the muscle to threshold. Action potential fires in the muscle

voltage gated channels current relationship with membrane potential experiment

Tease of the relationship between the voltage dependent currents using the voltage clamp Can do lots of voltage steps and then find the resulting currents X axis is the membrane potential Find the amplitude of initial inward response (mA/cm2 is a measure of how much current is flowing) Graph on right is the result of many voltage steps tested. The graph is wrong because it should be flat where circled.. there is no appreciable current when the membrane potential is smaller than membrane potential Early Inward membrane current is inward flux of positive ions (sodium) and the sign is negative Late Outward membrane current is outward flux of positive ions (potassium) and is positive sign This is what's underlying the action potential As just observed in the last example, no appreciable ionic currents flow at membrane potentials more negative than the resting potential. However, currents not only flow but also change in magnitudes for more positive magnitudes The early current has a U-shaped dependence on membrane potential , increasing over a range of depolarizations up to 0mV because decreasing as it depoarlizes further. Also no early current flows at +52mV which is the equivalent to the Na equilibrium potential in this case—indicates that early current can be attributed to Na flow into the membrane The late current however increases monotonically with increasingly positive membrane potentials

temporal summation

Temporal summation: inputs that arrive at the same location but at different times. Synaptic potential observed depends on the time constant of the cell. Short time constant would create two distinct EPSP. With a long time constant, that EPSP will long outlast the synaptic short synaptic current creating it. Takes so long that by the time the second transmission arrives there is still residual EPSP, so it just summates. Can allow you to bring cell to threshold.

Non-NMDA Glutamate Receptors

Tetrameric structure Bind glutamate Na and K ion channels Relatively low conductance (gamma is less than 20pS) Their reversal potential is 0mV—don't need a high membrane potential to allow ions to flow through They designate the early part of postsynaptic potential—open at low mV, first part of postsynaptic potential you see EPSC generated by AMPA receptors usually are much larger than those produced by other types of ionotropic glutamate receptors, so that AMPA receptors are the primary mediators of excitatory transmission in the brain

Reversal Potential of the End Plate Current Changes When Ion Gradients Change

The identity of ions that flow during the EPC can be determined using the same approaches used to identify the roles of NA and K fluexes in currents underlying action potentials. The reversal potential for the receptor is known. So, the identity of the ions that flow during EPC can be deduced by observing how the reversal potential of EPC compares with the equilibrium potential for various ion species. This was tested by changing the extracellular concentrations of different ion species and observing the effect it had on the reversal potential of the receptor. When external sodium is lowered, IV curve is effected; shows Na is involved. Same with potassium Tug of war. By changing these concentrations you are changing the reversal potentials of these ions. By lowering the external Na—lowers the reversal potential (Na outside concentration is more similar to internal). Increasing external potassium concentration—by increasing the outside, you make the outside more similar to the inside and thus bringing potassium reversal potential closer to zero. So the ACh channel receptor conducts BOTH sodium and potassium in the same molecule.

neural circuitry for gill withdrawl

The neural circuitry for this is known because it involves so few neurons. The touch and the shock both are received by receptors of sensory neurons. These either synapse onto the interneuron or the motor neuron itself to elicit the gill withdrawal behavior

glycine receptor

The receptors primary purpose as an inhibitory receptor is to allow chlorine ions to flow into the cell. Ionotropic

Ionotropic Glutamate Receptor

There are three types of ionotropic glutamate receptors: NMDA, AMPA, and kainate. The non-NMDA receptors are AMPA or kainate. Both types of glutamate receptors pass Na and K ions. Thus they always produce excitatory postsynaptic responses NMDA receptors have a Mg block that keeps the channel closed Ionotropic receptors: NT binds to receptor and causes conformation change that allows the ions to flow through Pic: sodium flowing in and potassium flowing out—excitatory like what observed in action potential

Electrical Synapse

These are much more prevalent than used to think but most of neuroscience focuses on chemical signaling Especially in invertebrates, electrical signals are also fairly important Mediated by gap junctions—direct connection between the cytoplasm of the presynaptic and postsynaptic cells Gap junctions exist throughout our bodies. Called an electrical synapse when these are found between neurons. Created by the two lipid bilayers of the two cells coming very close together Embedded in both membranes are connexon hexamers (6 connexon come together to form a unit). Created by connexon hexamers that line up between the cells. An atom is one angstrom—these two cells are 3.5 nm so that's like 35 atoms apart This allows the connexon from both sites to dock together and form permanent channel that is always open These connexons are always open Electrical synapses are the minority Found in all nervous systems and permit direct, passive flow of electrical current from one neuron to another Presynaptic is upstream element and postsynaptic is downstream Two are linked together by the gap junction. These contained precisely aligned paired channels called connexons. Present on both sides. Six align on one side with six on the other to form a pore that connects the two cells. Larger than pose in chemical synapses, which allows a variety of substances to simply diffuse between the cyptoplasm of the two; this permits ATP as well as important intracellular metabolites to be transferred between the two Work by allowing ionic current to flow passively through the gap junction pores from one neuron to another. The usual source of this current is the potential difference generated locally by the presynaptic action apotential Transmission can be bidirectional. Transmission is very fast because virtually instantaneous—no delay of chemical synapses Allows quick escape from predatory stimulus Also used to synchronize electrical activity among populations of neurons

Synapse

This is a point of communication between neurons First described by Ramon y Cajal - discovered these points of contact Named by Sir Charles Sherrington Electrical and chemical These two types of synapses are essentially two different ways of getting the message across

Signal Transmission in Crayfish

This is good for rapid transmission of signals Chemical synapses have more complicated machinery whereas electrical is just the direct flow of currents Used in emergencies to escape things when you need fast reaction time

Muscarinic ACh Receptor

This is linked to Gprotein This is a second class of ACh receptors Binding of ACh to this site causes a conformational change that permits G proteins to bind to the cytoplasmic domain of the mAChR Different subtypes of this receptor can cause a variety of slow postsynaptic responses.

Glutamate Significance

This is the predominant NT in the nervous system. Most important transmitter for normal brain function. Excitatory

steps in EPSP being longer than EPSC

Time 1: Receptor channel closed; no net current; resting membrane potential. Steady state. Switch is open on the equivalent circuit because nothing is bound to the receptor. Time 2: onset of synaptic action. Dynamic. Synaptic current flowing in through the ion channels. This current can go two ways: out through the leak channels or deposit on the plasma membrane (the capacitor). Initially very easy for these positive charges moving in to flow onto the capacitor. So initially you have big capacitive current that will make the inside less negative. This makes it more difficult for positive charges to continue flowing onto capacitor, so flow through the leak channels instead. Summary: receptor channel open, EPSP, leak, and capacitative current; capacitor discharging Time 3: Peak of synaptic action. Steady state. Eventually, no capacitive current flowing and all current is through the leak channels. Total current coming into the cell is starting to decrease with time because less binding of ligands. At all times the sum of the capacitive current and leak current is equivalent to synaptic current. Summary: channel open. EPSP and leak current. No capactive current. Capacitor stable. Time 4: Decline of synaptic activity. Dynamic. channel is closed. No more synaptic current coming in. Although there is no new current coming in, there is still situation when capacitor is charged. Still have less negative charge on the inside of cell. Circuit needs to rebalance during this time. To do so, positive charge that was deposited on capacitor need to go somewhere. Switch for circuit is off because no binding of ligands so can't go through there. Can only flow out through the leak channels. Equal and opposite currents through the capacitor and leak channel. Eventually brings the membrane potential back to rest. Summary: receptor channel closed. Leak and capacitive current. Capacitor recharging.

advantages of the voltage clamp

Too many variables are voltage-dependent in electrophysiology. When the membrane potential is not constant, there is a capacitive current; often to difficult ot accurately measure and hard to know the capacitance so that you can utilize the differential equation. (Ic= Cm * dV/dt) Channel activation states (open, closed, inactivated) are both voltage and time dependent. Not linear and is complex. But if you can control voltage you can start teasing apart these different mechanisms one by one.

structure of mammalian voltage gated K channel

Transmembrane portion that is embedded in lipid bilayer As part of membrane embedded region, there are a bunch of alpha helices that come together from various proteins to form the pore. Then other helices to form the voltage sensor Image B is looking down into pour. 4 subunits assemble to form the voltage gated K channel. The central pore of this region of this channel consists of two membrane spanning structures and pore loops contributed by each of the four subunits. This voltage gated channel has four additional transmembrane structure that form the voltage sensors of this channel. These voltage sensors can be observed as separate domains that extend into the plasma membrane and are linked to the central pore of the channel. The positive charges within these voltage sensors enable movement within the membrane in response to changes in membrane potential. Inward or outward forces of the sensors exert force on the helical linkers connecting the sensor to the pores, pushing the pore open or closed. Voltage sensors have net positive charges so that are either attracted or repelled to the interior of cell depending on its charge—this movement changes orientation of whole protein It is likely that other ion channel types similar to K channel in their functional architecture

Differential release of NT

Two classes: small molecule and neuropeptides They're also different in what causes their release In one presynaptic terminal you can have both a small molecule and neuropeptide in different vesicles Low frequency stimulation: localized increase in calcium concentration which will release the small molecule neurotransmitters. Neurotransmission. But the neuropeptides are not released with this low or medium level activation High frequency stimulation: longer train of action potentials results in channels staying open longer. More ca in nerve terminal and the signal can now reach other vesicles. small molecules and the neuropeptides are released. This causes bigger increase in calcium concentration that is not so local (more diffuse) and instead invading the entire terminal Local concentration of ca is important and regulates vesicle release

animal models of memory

Use animal models to more easily study Aplysia: sea snail used to study nonassociative learning (habituation and sensitization). Plasticity is so fundamental that the essential cellular and mocular underpinnings are likely conserved in nervous system of very different organisms

Patch Clamp Method

Used to understand voltage gated channels better. A wealth of new information about ion channels has resulted from the invention of the patch clamp method. In contrast to sharp electrode, this is a patch electrode that attaches to the membrane of the cell. A glass pipette with a very small opening is used to make tight contact with a tiny area, or patch, of neuronal membrane. After the application of a small amount of suction to the back of the pipette, the seal between the pipette and membrane becomes so tight that no ions can flow between the pipette and the membrane. Thus all the current that flows when a single ion channels opens must flow into the pipette. This current can then be measured. This allows for experimental control of the membrane potential to characterize the voltage dependence of membrane currents Minor manipulations allow for other recording configurations Allows you to contact and then record from an extremely small patch of membrane—great because ideally you'd end up with just one or a few ion channels in it which allows you to study an ion channel essentially in isolation

current clamp

We command (inject) a particular current into a cell. Current is controlled (independent variable) and the voltage is measured (dependent variable)

EPSP longer than EPSC

What currents operate at what time in the postsynaptic cell? EPSP longer than EPSC due to membrane capacitance EPSC creates EPSP once the receptor channel is open The current hits zero first while an EPSP is still exists. Has to do with the capacitor and the equivalent circuit. At the synapse, the combination of all the receptors creates the synaptic conductance (gsyn). All of the other channels create another conductance called conductance of leak (ge). Also have the conductance of the membrane. The fact that this postsynaptic potential is lasting longer than current is important for signal processing in neurons. If one cell have double the capacitance of another but they both have the same current. Tao= RC. How long this outlasts depends on the capacitance. Large C allows you to deposit a lot of charges onto the capacitor so it will outlast much greater. So response of cell depends on biophysical properties like capacitance. This is how nature can tune nerve cells is respond differently to the same input of information. How they respond to different information

short term facilitation

What is the neural basis of this memory? Have presynaptic and postsynaptic. Presynaptic causes EPSP (not action potential) in the postsynaptic. The second EPSP is larger in size—same presynaptic potential can elicit this larger amplitude. If you move these two signals very far apart—there is no effect. Both cause the same size EPSP. If you move the two signals very close together though, the amplitude will be quite a bit larger. Change over time of efficacy of synapse: plasticity There is some kind of memory trace. Definitely not declarative. Hypothesis of underlying mechanism is presynaptic calcium buildup. Calcium flows into cell to trigger NT release. If the two AP occur close enough in time, there is still some residual calcium in presynaptic terminal. So when the second action potential comes in, that new calcium that comes in is adding to an already elevated level of calcium. Creates even more NT release. Synapse based explanation of rudimentary memory. Synaptic connections between neurons are dynamic entities—constantly changing in response to neural changes and other influences. Chemical synapses are capable of undergoing plastic changes that either strengthen or weaken synaptic transmission. Short term forms of plasticity (which are those lasting for a few minutes or less) are readily observed during repeated activation of any chemical synapse Synaptic facilitation is a rapid increase in synaptic strength that occurs when two or more action potentials invade the presynaptic terminal within a few milliseconds of each other. By varying the time interval between presynaptic action potentials, it can be seen that facilitation produced by the first action potential lasts for tens of milliseconds. Much evidence indicates that this facilitation is the result of prolonged elevated presynaptic calcium levels following synaptic activity. Although Ca enters the cell within a millisecond or two of the action potential, the mechanisms to return Ca to resting levels are much lower. So when action potentials occur close in time, calcium builds up in terminal and llows more NT to be released by a subsequent presynaptic action potential Molecular target is synaptotagmin, which has a Ca sensor and causes vesicle fusion Experimentally how would you show increased Ca in nerve terminal? Increase extracellular concentration of Ca and calculate the postsynaptic membrane potential changes

Reversal Potentials and Threshold Potentials Determine Postsynaptic Excitation and Inhibition

What makes a synapse excitatory or inhibitory? Think about where is the reversal potential of that synaptic channel relative to the membrane channel PSP ultimately alter the probability that an action potential will be produced in the postsynaptic cell. PSPs are called excitatory (EPSP) if they increase the likelihood of a postsynaptic action potential occurring, and inhibitory (IPSP) if they decrease this likelihood. In both cases, NT bind to receptors to open or close ion channels in the postsyanptic cell. . The only difference between the two is the reversal potential of the PSP in relation to the threshold voltage for generating action potentials in the postsynaptic cell

Stimulate the motor axon in low extracellular calcium

When stimulate the motor axon. Sitting in solution of low calcium. Not much calcium will flow into presynaptic and lead to NT release. This results in potential that is below threshold. These subthreshold EPP are all different sizes. Sizes not distributed randomly. This smaller value allowed scientists to measure more accurately. Subthreshold because not enough calcium in surrounding area to release many. Number of vesicles released are way smaller than normal. The smallest evoked responsed and the MEPP are similar in magnitude. EPP is made up of many quantal MEPP

outside out patch clamp method

Whereas if the pipette is retracted while it is in the whole cell configuration, the membrane patch produced has the extracellular surface exposed. This is called the outside out recording configuration. Optimal for studying how extracellular chemical signals influence channel activity

working memory

Working memory: example is reciting a number sequence

LTP is based on

a large amount of evidence that seems to underlie learning and memory

Action Potential Conduction Requires both

active and passive flows All information discussed so far in the lecture has been ignoring the cable nature of the axon Na channels locally open in response to stimulus, generating an action potential here. Action potential at point A. There is a lot of sodium flowing into the cable—some of this depolarizing current passively travels down the axon as well as some escapes through leak channels. Note that this passive current flow does not require the movement of Na along the axon but instead occurs by shuttling of charge. This passive current depolarizes the adjacent region of the axon This local depolarization causes neighboring sodium channels to open and generates an action potential here. Creates a sort of cascade. Upstream sodium channels inactivate while potassium channels open. Membrane potential repolarizes and axon is refractory here The process is repeated, propagating the action potential along the axon. This explains the long distance transmission of these signals Thus, action potential propagation requires the coordinated action of two forms of current flow: active and passive Refractory periods occur because in the wake of an action potential, the Na channels are inactivated and the K channels are activated for a brief period of time

Ligand gated ion channels

also called ionotropic . These are receptors for neurotransmitters but they are also a channel. Both aspects contained within this same molecule. The binding of the neurotransmitter affects channel open capacities

Axocomatic

axon synapses on the soma

Axo-axonic

axon synapses onto another axon

ultrastructural components in electrical

connexins

Role of calcium: fluorescent dye

fluorescent dye that responses to calcium that was injected into presynaptic terminal and was depolarized. Look at response of calcium sensitive dye. Shows that the concentration of calcium increases when presynaptic terminal is depolarized

calcium

found that calcium is sufficient and necessary for NT release

Myelin

increases action potential conduction speed If you initiate an action potential at the same point in the myelinated vs unmyelinated—the myelin has already travelled to next node whereas in unmyelinated its only about halfway there Enables rapid propagation of action potentials across long distances How nervous system has evolved to quickly and effectively propagate signals By acting as an electrical insulator, myelin greatly speeds up action potential conduction

strong tetanic stimulation of a presynaptic

neuron induces long lasting changes in the efficacy of synaptic transmission with a post synaptic neuron

Axodendritic

normal synapse onto a dendrite

the hippocampus is

one important region for the formation of memories and exhibits LTP (among other brain regions)

ultrastructural components in chemical

presynaptic vesicles, postsynaptic receptors

implicit memory

remembering more how to do something like ride a bike. Reflexive in nature. Nondeclarative because you don't ever spell it out. Learned tasks, unconscious in nature. Includes priming, procedural, associative learning, nonassociative memory

NT categories

small molecules and neuropeptides

explicit memory

straight up facts you store. Includes both facts and events. Involves the medial temporal lobe. Conscious awareness. Can be expressed in language

histology

studying the structure of the cell. Can also provide evidence of NT

glycine

the other primary inhibitory NT GABA is present mainly in the brain whereas glycine is located in the brain stem and spinal cord primarily (still present in the brain some too though)

GABA synapse

there are also inhibitory synapses, and the most common of this GABA. Here, the reversal potentials of these channels is negative. This is because these channels are conducting Chloride so their reversal potential is the Cl reversal potential. These channels open up and conduct chloride into the cell to lower the voltage. This makes the inside more negative and thus hyperpolization (IPSP= inhibitory). Less likely to reach action potential threshold. In some cells, the GABA reversal potential, this is actually above Vrest. So, inhibitory synapses need not produce hyperpolarizing IPSPs. Seen during early development. Depolarized relative to in the adult. Now if you apply GABA it opens channels and chloride ions will move out of the cell to make the inside positive. So depolarization results. This is not excitatory despite making the membrane more positive. This is because even if you open all the chloride channels, it can only get you to -50mV (its reversal potential) which is not threshold anyways. So it is inhibitory by keeping the postsynaptic membrane potential more negative than the threshold potential. So can never actually cause an action potential. Also causes shunting (leaky). So if another synapse comes in to excite then most of the curent is wasted

LTP can be broken down into

three phases based on the molecular evens occurring within the cell

En passant

two axons touching each other in passing and don't form swollen presynaptic density but can still have activity