MCDB 151 Week 5

Many proteins are involved in docking/priming

(the mechanism of docking/priming is not well understood)

In central synapses, measuring mini Excitatory Postsynaptic Potentials (mEPSPs) and Currents (mEPSCs) is a useful tool for studying neurotransmission and plasticity

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Peptide neurotransmitters are often co-released with particular small molecule neurotransmitters

-Acetylcholine VIP Substance P -Norepinephrine Galanin Enkephalin Neuropeptide Y -Epinephrine Neuropeptide Y Neurotensin -Dopamine Cholecystokinin Neurotensin -Serotonin (5-HT) Substance P TRH Enkephalin -GABA Somatostatin Cholecystokinin Neuropeptide Y

Clathrin structure and vesicle endocytosis

1. Adaptor proteins connect clathrin to vesicular membrane. 2. Clathrin triskelia assemble into coat, curving membrane 3. Dynamin ring forms and pinches off membrane 4. Coated vesicle translocated by actin filaments 5. Hsc--70 and auxilan uncoat vesicle

ACh receptors (AChR)

2 types - Ionotrophic -CNS version and also Metabotropi - CNS version focus as well

Metabolism of ACh

ACh is degraded by acetylcholinesterase (AChE), a soluble enzyme enriched at the synaptic cleft One AChE molecule can degrade ~5000 molecules of ACh per sec (highly efficient) After AChE-mediated degradation, both acetate (not shown) and choline are re-uptaken by the presynaptic neuron for the synthesis of new ACh -Once it is released (acetylcholine) it needs to be recycled - i ti s degraded by AChE - hight concentration in synaptic cleft - gets brought back in, made inactive and then turned into new acetylcholine - dimentia - thought to be due to acetylcholine esterase - it breakdowns acetylcholine

Synthesis of ACh

ACh is synthesized from Acetyl CoA and choline by choline acetyltransferase (ChAT), with choline as the limiting molecule -through enzyme acetylcholine will be loaded into vesicles - each NT will have its own transporter - ChAT - Accetytransferase

Summary

Acetylcholine Small molecule transmitter with ionotropic and metabotropic receptors • Primary motor neurotransmitter in PNS via nAChRs • in CNS, has neuromodulatory functions via mAChRs Biogenic Amines (DA, NE, Epi, 5-HT) Autonomic functions in PNS, neuromodulatory functions in CNS • Catelcholamines share common synthesis pathway from Tyrosine precursor, serotonin derived from tryptophan • Receptors are generally metabotropic

Midbrain dopamine is important for reward processing

Addiction: Compulsive pursuit of rewarding stimuli, despite adverse consequences Believed to arise from "hijacking" of endogenous reward system by pharmacological agents (most addictive drugs increase DA or NE signaling) if you stimulate the reward part of brain in an animal the animal peaks its nuts off without actually having a nice experience or reward

Metabotropic Purine Receptors

Adenosine receptor Inhibits PNS function (vasodilation, heart rate) and CNS function (midbrain dopamine)

Metabotropic AChR

Also called muscarinic AChR (mAChR1-5) - binds to muscarine Regulatory functions in Autonomic Nervous System (e.g., slow heart rate) Modulates neural activity in CNS, (function less understood)

Ionotropic AChR

Also called nicotinic AChR (nAChR) - binds to nicotine Excites skeletal muscle in PNS Used for signaling in basal ganglia of CNS (likely mediates nicotine addiction)

Summary

Amino Acid transmitters (Glutamate, GABA) • Principle excitatory and inhibitory neurotransmitters in CNS • Bind to ionotropic and metabotropic receptors Purines (ATP, adenosine) • Bind to ionotropic and metabotropic receptors, important for autonomic functions, apoptosis, pain responses Neuropeptides • Different transport and release properties • Diffuse, long-lasting modulation (more global signaling)

Amino Acid Neurotransmitters

Amino acids are organic compounds with fixed amine and carboxyl groups, and a unique side chain [R] specific to each amino acid About 90% of synapses in the brain use amino acid NTs gluatamate - 70% of synapses - GABA - 20-30% of synapses use it - ABOUT 90% of synapses use amino acid NTs

Synapsin anchors vesicle to F-actin as the reserve pool at low [Ca2+]

At high [Ca2+], CaMKII (a Ca2+-dependent kinase) phosphorylates synapsin and inhibits its interaction with F-actin --As a result, Ca2+ also regulates the mobilization of reserve pool to support on-going neurotransmission via synapsin

Peptide neurotransmitters have different biogenesis and transport mechanisms

Both enzymes and precursors are made in soma and packed into secretory vesicles at the ER --> The secretory vesicles are transported to terminus via fast axonal transport The enzymes convert the precursors to peptide transmitters during transport-->Large dense-core vesicles are ready for release at terminus ONLY RELEASED AT HIGH LEVEL OF STIMULATION

Peptide Transmitters

Both enzymes and precursors are made in soma and packed into secretory vesicles at the ER --> the secretory vesicles are transported to terminus via fast axonal transport -> the enzymes convert the precursors to peptide transmitters during transport --> Large dense core vesicles are ready for release at terminus

Biogenic Amines in the CNS

CNS neurons releasing biogenic amines are mainly found in the midbrain (axons are project to a variety of brain areas). These neuromodulator systems are important for controlling mood, arousal, and reward. Biogenic amines are important targets of psychotherapy & addiction: Depression (hypothesized to be caused by a decreased level of 5-HT) Addiction (caused by an increased level of dopamine) -Note that biogenic amines also play important roles in PNS, such as gut function (5-HT) and autonomic functions (NE and Epi)

A principle function of synaptic vesicles enabling Ca2+ - triggered neurotransmitter release (called fusion)

Ca2+ couples AP to transmitter release by promoting the fusion of vesicle with membrane

Terminology (using Acetycholine as an example)

Cholinergic neuron: a neuron which synthesizes and releases ACh Cholinergic synapse - a synapse where ACh is the NT Similar terminology is applied to other NT (eg glutamatergic, GABAergic, dopaminergic)

VGLUT is H+ -dependent glutamate transporter which loads glutamate into vesicle using the pH gradient

Different neurotransmitters use different vesicular transporters

Alternative (faster) recycling pathways exist

Direct recycling (no endosomes involved) - faster Kiss and run exocytosis (partial fusion followed by vesicle resealing, no internalization involved) - fastest

Docking is a process in which vesicles are localized to the presynaptic membrane in a fusion-ready state

Docking and priming facilitate the formation of the SNARE complex to prepare for transmitter release

NMDA Receptors and Synaptic Plasticity

Donald Hebb "Cells that fire together, wire together" (Hebb's Law) Paraphrase of Hebb's The Organization of Behavior (1949) NMDA receptors Have unique properties that allow them to serve as coincidence detectors for presynaptic release and postsynaptic depolarization (in accord with Hebb's Law)

Proteolytic processing of a pre-propeptide into multiple peptide neurotransmitters in the secretory pathway

ER ER> Golgi> Vesicles Vesicles ER ER>Golgi>Vesicles Vesicles Proteolytic processing of a pre-propeptide into multiple peptide neurotransmitters in the secretory pathway

The importance of excitatory/inhibitory balance

Excessive excitation leads to epileptiform activity Exact mechanism not known (probably several), but thought to involve disruption of inhibition in many cases Treatment: GABA agonists such as benzodiazepines and barbiturates GABA agonists also used as sedatives, anesthetics Alcohol also alters GABAergic activity, causing some of the observed symptoms (slurring, incoordination, CNS depression)

Key Concept: Binding-induced conformational change represents a common way to regulate a protein's function

For Example: • Binding of Ca2+ to Calmodulin/CaMKII causes phosphorylation of synapsin, leading to the mobilization of vesicles • Binding of Ca2+ to synaptotagmin leads to insertion into membrane

Fusion: When two separate lipid bilayer membranes merge into a single continuous membrane

Fusion leads to the release of neurotransmitters into the extracellular synaptic cleft, yet the lipids and membrane proteins of synaptic vesicles are preserved Fusion --> Cytoplasmic side - extracellular/lumen side --Since the membrane topology is conserved before and after fusion, the topology of membrane proteins is also conserved

Major types of peptide neurotransmitters

Generally, neuropeptide receptors are high-affinity metabotropic receptors (why?) lots of addictive potential

Histamine is derived from histidine (an amino acid) - one function of histamines is to increase vascular permeability - what effect might this have?

Histamne - a modulatory NT - involved in vascular permeability - this effects the process of congestion -

What happens to internalized vesicles after uncoating?

Horseradish peroxidase (HRP) can be used to follow the fate of internalized vesicles extracellular coated buds/vesicles endosomes synaptic vesicles These experiments showed that at least a fraction of internalized vesicles are recycled through endosomes in the presynaptic terminus HRP is an enzyme that converts its substrate into a colored product (1) HRP briefly added to the medium (then washed out) (2) Internalized HRP localized by adding substrate at different time points

In addition to Botulinum and Tetanus toxins, a number of potent neurotoxins target neurotransmission (for your info: you don't need to memorize these)

In addition to Botulinum and Tetanus toxins, a number of potent neurotoxins target neurotransmission (for your info: you don't need to memorize these)

The life cycle of vesicle

In addition to fusion, vesicle-associated and presynaptic proteins also modulate other steps during the vesicle life cycle

But SNARE proteins do not bind to Ca2+, how do they mediate Ca2+ dependent fusion?

In addition to v-SNAREs, there are many other proteins on the vesicle (diagram illustrates 70% of the proteins on a glutamate vesicle)

ACh receptors (AChR)

Ionotropic AChR- 5 transmembrane units that bind to cause conformational change and opens up pore - allows cations to flow Metabotrophic - 6 units once acetylcholine binds it opens a cascade of ions

GABAergic receptors

Ionotropic GABA receptors GABAA receptors Selective for Cl- ions Usually inhibitory (IPSP) except early in development - why? Metabotropic GABA receptors GABAB receptors Comprised of heterodimers of B1 and B2 subunits Results in opening K+ channels and closing Ca2+ channels - effect? Also increases cAMP levels ionotropic - selective for Cl- → it hyperpolarizes the cell → the ECL becomes negative - early in development there is an exception because - different [gradients] lead to different results

Purine Receptors

Ionotropic and Metabotrophic why important for pain and apoptosis - answer: why ATP - important because skin just got ripped apart or burned them- ATP gets spilled out Adenosine receptors blocker - caffeine coffee

Overview of the Vesicle Lifecycle:

Loading, mobilization, docking, priming, fusion, recycling

Evidence for the presence of NTs at a chemical synapse

Loewi's Experiment (1926) - Soluble molecule from Heart 1 diffuses to lower tank; slow rate of Heart 2 (diffusible chemical later found to be ACh released by Vagus nerve) Acetylcholine first ever NT found

Midbrain serotonin is important for mood regulation

Major Depression: Thought to be caused by decreased level of serotonin from Raphe Nucleus Treatment: • Tryptophan: Disputed effectiveness, can be toxic in higher doses (Eosinophilia-myalgia syndrome) • SSRIs (e.g., Prozac, Zoloft): Selective serotonin reuptake inhibitors increase available 5-HT in synaptic cleft • MAOIs: MAO inhibitors prevent degradation of 5-HT, increasing amount in cleft

After neurotransmission, the cell needs to rapidly regain ability to release NTs

Mech: 1. Back-up pool of synaptic vesicles at the presynaptic terminus 2. Ongoing recycling of synapti vesicles and NT 3. Reactivation of postsynaptic receptors

Neurotransmission needs to be transient (otherwise temporal information would be lost)

Mechanism: 1. Rapid removal of intracellular Ca2+ in presynaptic terminal 2. Rapid removal/recycling of released NT in cleft 3. Rapid inactivation of postsynaptic receptors

Neurotransmission needs to be fast (otherwise temporal information would be lost)

Mechanisms: 1. High density of presynapti Ca2+ channels 2. Ready-to-release synaptic vessel 3. High density of postsynaptic receptors

Summary

Neurotransmitters can be small molecules or peptides: • Small molecule transmitters are synthesized locally and are involved in fast communication between neurons (e.g., glutamate, GABA, ACh, Dopamine) • Peptide transmitters are transported from the soma and are generally involved in slower regulatory/modulatory functions (e.g., neuroendocrines, opioids) Fusion is the process by which vesicles release neurotransmitter into the synaptic cleft: • Fusion is a Ca2+-dependent process • Fusion is mediated by SNARE proteins on vesicle and membrane surface

Ionotropic Purine Receptors

P2X receptor Unusual structure: 2 TM domains per subunit, receptor is a trimer Important for: autonomic functions, nociception (pain sensation), and apoptosis (why pain and apoptosis?)

Synthesis of glutamate (no need to remember entire biosynthetic pathway) The major synthesis pathway (shown here): glutamine precursor Other synthesis pathways: glucose or pyruvate precursors (using different enzymes)

Packaged into vesicles via the VGLUT transporter through reuptake receptors it goes back and recycled - it gets picked up by EAT - it is brought back into precursors - back in presynaptic terminal

Midbrain dopamine is also important for motor coordination

Parkinson's disease: Caused by a decreased level of dopaminergic input from substantia nigra (midbrain) to basal ganglia Treatment: What strategy could be taken to increase dopamine production in Parkinson's patients? L-DOPA (dopamine precursor) - Most widely used medication for Parkinson's disease - motor coordination important to stimulate in order to help with parkinsons or something like that - answer to question: give them precursor DOPA - elDOPA - crosses BBB well and increases dopamine - you cant just add dopamine but you can increase it useing elDOPA

2.

Peptide NTs: -Pituitary peptides, hypothalamic peptides (neuroendocrine) -Substance P, opioid peptides and others (pain) -Play important functions, but peptide transmitters are not generally involved in neural processing)

Presynaptic Localization Partially determines how presynaptic activity affects release

Peptide transmitter vesicles are at a distance away from the synapse Small molecules transmitter vesicles are closer to synapse - Small molecule neurotransmitter in small clear-core vesicles -Neuropeptide in large dense-core vesicles Localized increase in Ca2+ concentration -More diffuse increase in Ca2+ concentration

Small molecule and peptide transmitter vesicles have different presynaptic localizations

Peptide transmitters vesicles are at a distance away from the synapse - Small molecule transmitter vesicles are located closer to synapse

Acetylcholine (ACh) - (Ch3)3N+-CH2-CH2-O-C=0-CH3

Primarily an excitatory neurotransmitter (definition?) (ionotropic receptors are non-selective cation channels, metabotropic receptors can have more complex responses) • Primary neurotransmitter used in the PNS motor neurons • One of the primary neurotransmitters used in the autonomic nervous system (along with norepinephrine) • Acetylcholine's CNS function is more modulatory and less well understood

Glutamate (Glu)

Principle excitatory neurotransmitter in CNS (when bound to ionotropic receptors, metabotropic receptors can have more complex effects) As the major excitatory neurotransmitter in the CNS, ~70-80% neurons (the vast majority of excitatory neurons) release glutamate as their primary neurotransmitter Additional (less common) excitatory amino acid neurotransmitters include: Aspartate, Cysteine, Homocysteine Glutamatate- majority by ionotropic receptors - BUT It is different in PNS - these values are for CNS only

γ-aminobutyric acid (GABA) (Gamma - y)

Principle inhibitory neurotransmitter in CNS (when bound to ionotropic receptors, metabotropic receptors can have more complex effects) As the major inhibitory neurotransmitter in the CNS, ~10-20% neurons (the vast majority of inhibitory neurons) release GABA as their primary neurotransmitter Additional (less common) inhibitory amino acid neurotransmitters include: Glycine, β-Alanine, Taurine

Purine Neurotransmitters

Purines (e.g. ATP, adenosine) can act as neurotransmitters. ATP is contained in all synaptic vesicles and often acts as a co-transmitter. However, it can also act as a primary neurotransmitter. Adenosine is a product of ATP degradation in the synaptic cleft and has unique signaling actions through adenosine receptors; not considered a classical neurotransmitter --- packages vesicles are by themselves

Metabolism of GABA

Re-uptake pathway: GABA transporters (GAT) remove GABA from cleft for breakdown into glucose or glutamate Astrocytes play an important role in GABA recycling

Metabolism of Glutamate

Re-uptake pathway: via excitatory amino acid transporters (EAATs) in both neurons and glial cells Astrocytes play an important role in glutamate recycling

Biogenic Amine Receptors Almost exclusively metabotropic (exception: 5-HT3R)

Receptor Norepinephrine and epinephrine bind to the same receptors (with different affinities)

Reserve and Readily Releasable Pools of vesicles

Reserve pool is kept away from the presynaptic membrane Readily Releasable Pool -Reserve Pool --> mobilization --> readily releasable pool -Mobilization triggered by increased cytoplasmic Ca2+

Serotonin is derived from tryptophan (amino acid) -One function of serotonin is to regulate sleep, what effect would you expect from consuming a 5-HT precursor?

Serotonin is derived from tryptophan - makes you more sleepy

The synaptic transmission at the NMJ only involves one type of neurotransmitter, ACh, and one type of neurotransmitter receptor, AChR

Since the synapse of the NMJ is located on a specialized postsynaptic membrane called the motor end plate, the PSCs (postsynaptic currents) and PSPs (postsynaptic potentials) in NMJs are called the EPC (end plate current) and the EPP (end plate potential)

Two Major Types of Neurotransmitters

Small Molecules: -Acetycholine -Biogenic Amines -Amino Acids -Purines Peptide Transmitters: -Endogenous peptides Unconventional: -Endocannabinoids -Nitric Oxide

Two major types of Transmitters with Different Structures:

Small molecule NTs: -Amino acids: Glutamate, GABA, glycine and others -Monoamines: Dopamine, -Norepinephrine, Serotonin Purines: ATP, Adenosine Acetychloine -Crucial for information processing and muscle contractions

Small molecule and peptide transmitter have different biogenesis and transport mechanisms

Small molecule transmitters: -Precursors found in the axonal terminus but synthesis enzymes made in the soma --> the enzymes are cytoplasmic proteins transported to terminus via slow axonal transport--> -The enzymes convert precursors into transmitters at the axon terminus -->transmitters loaded into vesicles via transporters on vesicle surfaces --> -loaded into small clear core vesicles

Small molecules and peptide transmitters play different roles in neuronal communication

Small molecule transmitters: Released in response to lower frequency activity mediating rapid transient synaptic actions Peptide Transmitters: Released in response to higher frequency activity mediating slower ongoing synaptic actions General rule (not absolute)

After fusion, vesicles are recovered in a multi-step recycling process

Step 1: Following fusion, the protein clatharin coats vesicles in order to recover from presynaptic membrane Step 2: After coating, the protein dynamin pinches off coated vesicle from membrane Step 3: After coated vesicles are dissociated from membrane, several proteins (Hsc-70, Auxilin, synaptojanin) remove the clathrin coating form the vesicle

Synthesis of GABA

Synthesis pathway: Glutamate is converted to GABA by Glutamic acid decarboxylase (GAD) Packaged into vesicles via the VGAT (VIATT) transporter

Given the critical role of SNARE in fusion, the SNARE machinery is the target of several neurotoxins

Tetanus toxin: blocks release specifically in inhibitory neurons, causing spasms Botulinum toxin A ("Botox"): Used for cosmetic reasons, but also for migraines and muscle spasms

A model of how the vesicle-bound synaptotagmin protein binds to Ca2+ and catalyzes fusion

The binding of synaptotagmin to Ca2+ is thought to cause: 1) The binding of synaptotagmin to SNAREs 2) The insertion of its cytoplasmic domain into the pre-synaptic membrane 3) Opening of the fusion pore Synaptotagmin thought to function as a Ca2+ sensor during fusion (How Ca2+ mediates fusion is still an area of active investigation)

Using electrophysiology to measure neurotransmission at a chemical synapse

The neuromuscular junction (NMJ) is ideal for characterization of the chemical synapse (NMJ is large, simple, and accessible) The synaptic transmission at the NMJ only involves one type of neurotransmitter, ACh, and one type of neurotransmitter receptor, AChR

summary

The vesicle lifecycle allows vesicles to play multiple roles in neurotransmitter release: • Vesicles can be preloaded in reserve pools or in a readily releasable state • After they undergo fusion, they are recycled in a multi-step process Quantal release of neurotransmitter • Quantum can be measured using mini postsynaptic events • Frequency and amplitude of mini postsynaptic events can tell you about whether changes are presynaptic or postsynaptic

"Quantized" distribution of EPP amplitudes evoked in a low extracellular Ca2+ solution

These EPPs are integer multiples of 0.4 mV (quantal not continuous) 0.4 mV is thus the smallest potential that can be recorded and represents the building block of EPP (called the miniature EPP, or MEPP) The MEPP is thought to be the response to a single vesicle of neurotransmitter

What happens to internalized vesicles after uncoating?

These experiments showed that at least a fraction of internalized vesicles are recycled through endosomes in the presynaptic terminus

The surface of the vesicle is densely packed with proteins (in addition to SNAREs and synaptotagmin)

These proteins have additional functions beyond fusion

Metabotropic glutamate receptors

Three classes (I, II and III) with different subunit compositions Can excite or inhibit postsynaptic neurons (via 2nd messenger pathways) Often inhibit K+ and Ca2+ channels Involved in synaptic depression

Ionotropic Glutamate Receptors

Three classes: AMPA, NMDA, and Kainate receptors Always excitatory (EPSP) Non-selective cation channels (Na+ and K+, and sometimes Ca2+) Involved in synaptic potentiation

The quantal release of transmitters

Transmitters are released into a synapse in packaged vesicles called quanta: A quantum (i.e. the contents of a single vesicle) is the smallest amount of neurotransmitter that one neuron can release to its target

Snare Proteins form a Snare complex to drive fusion

Two types of SNAREs: t-SNARES and V-SNARE (t=target, v=vesicle) The SNARE complex consists of one v-SNARE and 2-3 t-SNAREs Important v-SNARE: synaptobrevin Important t-SNAREs: syntaxin and SNAP25 Important v-SNARE: synaptobrevin Alternative nomenclature (for your knowledge): R-SNAREs (acting as v-SNAREs) / Q-SNAREs (acting as t-SNAREs)

When a motor neuron is stimulated in physiological conditions, the resulting EPP is generally sufficient to generate an AP

Under physiological conditions: Motor neuron AP-> Fusion of many vesicles-> Release of a large amount of ACh-> Activation of a large number of AChR-> Large EPP (higher than threshold)-> Action potential

Peptide neurotransmitters have different biogenesis and transport mechanisms

Unlike small molecule neurotransmitters, commonly more than one active peptide neurotransmitter can be found in one vesicle

Peptide NTs release is diffuse and lost lasting

Unlike small molecule neurotransmitters, peptide neurotransmitters are often released extrasynaptically and degraded by extracellular enzymes (at a slower rate than small molecule neurotransmitters). As a result they have longer half lives and mediate long-lasting events can work at a longer distance (as hormones) lots of calcium needed to release it - once it is released it is extracellanaptyically -

CAn multiple neurotransmitters be loaded in the same neuron and/or vesicle?

Yes - different NTs can be released from the same neuron or the same vesicle - different terminals release different NTs - ATPs is in all vesicles - it is a cotransmitter but sometimes it is released by itself - this stuff is determined by the pump-gated channels

Thought experiment

You are studying synaptic transmission at a chemical synapse. After a brief depolarization of the presynaptic neuron, you recorded a fast EPSP followed by a slow IPSP. However, after repeated presynaptic stimulation, you observe a late, long-lasting EPSP. What do you think might have caused these different post-synaptic potentials?

What prevents glutamatergic neurons from releasing GABA? What prevents GABAergic neurons from releasing glutamate

answer: 1. Lack enzyme not going to get GABA 2. You need a GABA transporter to get into vesicle Answer Q2 - they dont have a vesicle transporter - GABAergic will lack transporter

Questions to Answers from Last Slide

answer: fast EPSP = glutamate bound to ionotrophic Slow IPSP - GABA and bound to metabotrophic receptor Long lasting EPSP - neuropeptides

Neurotoxins and mAChRs

atropine (belladonna) - mAChR antagonist - ANS effects, delirium and memory defects at higher doses scopolamine (henbane)

If all catecholamines are derived from the common precursor Tyrosine, how do different neurons make different catecholamines (some only make dopamine, some only make norepinephrine, yet others only make epinephrine ?

depends on the enzyme that one has

Catecholamines are derived from Tyrosine (amino acid)

hydroxylation - decarboxylation - hydroxylation - amine methylation

Biogenic amines

it is made inside the cell - nitrogen group at the end of structures Biogenic amines are derived from amino acids such as: Tyrosine, Tryptophan, and Histodine

Neurotoxins and nAChRs

lots of drugs/poisons that affect the neuromuscular junction and the acethylcholoine receptors a-bungarotoxin (krait snakes) - NMJ nAChR antagonist - Paralzye Prey a-conotoxin (cone snails) - NMJ nAChr antagonist - Paralze Prey arecoline (betal nuts) - CNS nAChR agonist - Euphoria/relaxation

Donald Hebb

mediocre scientist - neurons create a system that fires together - and so neurons that wire at same time - they link up and create faster reactions + cells that fire together, wire together - it stores info - they link up through NMDA receptors - in resting state it has a property that magnesium comes in and clogs the pore - and so when it depolarizes, the magnesium is driven out of the pore (why? Because the inside of the cell becomes more +) - now that the pore is clear - the cations can rush in and now calcium can trigger a ton of downstream effects → stronger neurons

What strategy could be taken to increase serotonin levels in depressed patients?

midbrain serotonin - mood regulation - answer: MAO inhibitor -

In absence of motor neuron stimulation or during presynaptic stimulation under low extracellular [Ca2+] much smaller subthreshold EPPs can be observed

no presynaptic stimulation under normal extracellular [Ca2+] GRAPH presynaptic stimulation under low extracellular [Ca2+] GRAPH These "mini" EPPs are much smaller than the EPPs observed under normal physiological conditions (>100mV) and they do not trigger APs

Midbrain dopamine is important for reward processing

powered and controlled the mouse and its direction

Glutamate Receptors

three major categories - AMPA and NMDA are the big ones - - always polarized - Metabotrophic - not exactly excitotory - depresses synapses- making them weaker

Peptide transmitters are important for:

• Modulating emotions • Social behaviors (sexual/parental) • Feeding/drinking • Stress reactions • Pain perception • Brain/gut interactions "secret message versus public announcement"

Metabolism of Biogenic Amines

• Re-uptake by DA/NE transporters (DAT/NET) • Degradation by MAO and COMT in neurons • Re-uptake by 5-HT transporters (SERT) • Degradation by MAO in neurons - different from acetylcholine because it is brought into astrocytes - histamine is broken down by MAO -