Neuro 3010 exam 3

purkinje neurons in response to climbing fiber

far more complex; shows an initial spike and multiple after; if you stimulate a climbing fiber within a set period of time followed by stimulation of a parralel fiber, there is a delay in firing pattern of cerebellar cells Increases in climbing fiber activity leads to decrease in simple spike activity

Rimonabant

first selective CB1 blocker approved for use. CB1 antagonist Pulled from market due to increase risk for severe depression and suicidal thoughts

LTD in the cerebellum

form of associative synaptic plasticity in which in-phase activation of parallel fibers and climbing fibers, at low frequency for 2-5 min, results in a sustained depression of parallel fibers that were active during the conjunctive stimulation No change in climbing fiber synaptic drive LTD can't occur in a hyperpolarized cell

granule cells in the cerebellum

form parallel layer that passes by purkinje cells

Glutamate receptors and excitotoxicity

glu is more abundant NT and also the most toxic in multiple injury and disease conditions, neurons release too much glu and initiate excitotoxicity Excitotoxicity is dependent on activation of glutamate receptors

Blood supply

highly vascularized strong connection between energy demand and supply in brain neurovascular (blood flow) and neurometabolic (glucose) coupling constitute the basis for function brain imaging techniques

ischemic stroke

inadequate blood supply a blood vessel supplying the brain becomes blocked (such as by a clot)- 87% of strokes

Ultra-Short term synaptic plasticity synaptic facilitation

increase in synaptic strength induced by 2 or more action potentials occuring in the presynaptic terminal within a few msec of each other a pair of presynaptic aps produced EPSP in postsynaptic neuron; second EPSP increased/facilitated interval or timing between presynaptic action potential is inversely correlated with amount of facilitation dur to prolonged elevation of presynaptic calcium levels following synaptic activity allowing more transmitter to be released. Mechanism to remove calcium is fairly slow and involved metabolic pumps

Endocannabinoid Synthesis

induced by activation of calcium permeable ionotropic NT receptors to induce calcium influx or metabotropic NT receptors that induce Gq activation (PLC)

Ischemic Stroke (middle cerebral artery)

infarction within MCA territory is most common site cortical branches of MCA supply 2/3 of the lateral surface of the hemisphere and temporal pole primary motor and sensory area of upper extremity and face broca's and wernicke's language areas in the dominant hemisphere effect contralateral side of the body; exact location of the blockage and area where blood supply is inadequate will determine symptoms

Oxidative damage can cause...

inflammation and proliferation changes in signal pathways that chagne gene expression damage DNA, mitochondria, and lipids exogenous factors can be: lifestyle, environmental conditions, stress conditions

Memantine

uncompetitve inhibitor of NMDA receptor displays voltage-dependence like magnesium ions Thought to inhibit the prolonged calcium influx which forms the basis of excitotoxicity low affinity and uncompetative nature preserves normal function

Endocannabinoid Action

1. NT release activates receptors that activate phospholipase C (2-AG) or Phospholipase D (AEA) Increase in calcium can also stimulate synthesis 2. Endocannabinoids leave the cell 3. Endocannabinoids interact with receptors on the presynaptic membrane which initiate activation signal transduction cascades to have a variety of effect on proteins in the presynaptic terminal Generally CB1 activation inhibits NT release through a variety of mechanisms

first 3 reasons the nervous system is vulnerable

1. an extremely complex array of NTs, NT receptors, ion channels, cell adhesion molecules, are required for normal functioning of the nervous system 2. 80% of known genes expressed in the brain (prone to alterations due to genetic mutations) 3. Proper organization is essential for normal function (brain continues to develop into the mid-20s) very dynamic

2 AG production

1. calcium increases in the postsynaptic terminal (through calcium permeable ionotropic receptors or depolarization-induced activation of postsynaptic voltage-gated calcium channels) This activates the enzymes responsible for generating 2AG 2. Stimulation of postsynaptic G protein couples receptors coupled to Gq (metabotropic gluatamte receptors, muscarinic receptors, etc)

necrosis

1. cell sells 2. cell becomes leaky, blobbing 3. cellular and nuclear lysis causes inflammation

apoptosis

1. cell shrinks, chromatin condenses 2. budding occurs 3. apoptotic bodies are phagoztosed by immune cells -no inflammation!

disruption of ionic gradients disrupt glutamate reuptake

1. disruption of ionic gradients decreases the driving force for sodium in and potassium out of cell 2. intracellular glutamate concentrations are high 3. cause the transporter to reverse directions, moving glu and Na out of cell and potassium into cell

nitric oxide cycle

1. increased levels of calcium in postsynaptic cell (due to opening of NMDA channels, release from intracellular stores, open voltage gated calcium channels) 2. activates nitric oxide synthase (NOS) 3. Uses arginine to produce NO and citrulline 4. NO diffuses across membrane to influence other cells and glia 5. induces an increase in cGMP in neurons and glia and/or nitrosylates proteins

retrograde tranmission steps

1. initiated in the postsynaptic terminal by an increase in cytosolic calcium 2. messenger is synthesized (right before release) and released from the postsynaptic terminal 3. messenger diffuses across the cleft and interacts with proteins in/on the presynaptic terminal 4. this induces changes in presynaptic activity

Because Nitric Oxide freely diffusees across membrane:

1. it can not be stored in vesicles. Once made- it freely diffuses out of cell 2. it's entry into other cells can not be controlled. It freely diffuses into all surrounding cells 3. productions of NO, then, is the rate limiting step in NO signaling

Basic Principles of Learning

1. multiple memory systems are present in the brain 2. short term changes in learning and memory require changes in existing neuronal circuits 3. these changes may involve multiple mechanisms within individual neurons 4. second messenger systems play a role in mediating cellular changes 5. changes in membrane channels are correlated with learning and memory 6. long term memory requiers new protein synthesis, short term memory does not

Two accepted areas where new neurons are routinely made

1. olfactory bulb (smell) - stem cells exist in subventricular zone to differentiate into interneurons within oflactory bulb -still nto entirely accepted in human brains 2. hippocampus (learning and memory). Stem cells in dentate gyrus of the hippocampus differentirate into granule cells and make new neurons (unknown if its occuring in adult humans

Hypothesized Events in Hippocampal mossy fiber LTP

1. presynaptic kainate receptors and MGLUR1 receptors are activated by NT release 2. PKA stimulation (mediated by increase in Ca concentration and activation of calcium-stimulated adenylate cyclase) 3. PKA induced phosphorylation of target proteins involved in synaptic vesicle fusion and transmitter release machinery 4. leads to an increased probability of transmitter release as well as possible recruitment of new or possibly silent sites 5. new protein synthesis and maintenance of LTP PRESYNAPTIC POTENTIATION

excitotoxicity and NO

1. toxic effects of NO are mediated by ONOO-ion 2. excess calcium also activates calcineurin and calpain (subsequent stimulates ROS) 3. excessive calcium or generation of ROS induced activation of mitochondrial permeability transtion and release of calcium and proapoptic factors in cytosol

What are endocannabinoids?

2 types: anadamide and 2-AG neuromodulatory lipids (2-AG is much more abundant) endogenous cannabinoids

Neurons are sensitive to insult

6. neurons display an inability to respond to injury (some neurons do recover, some don't) 7. many neurons require trophic support (some neurons die without appropriate signals to live) trophic neurons are helper molecules (help neurons maintain connections with neighbors need constant level of trophic to live

long term sensitization mechanisms

Activates cAMP/PKA cascade -- induces gene transcription; protein synthesis inhibits ApCAM which allows formation of addiitonal synapses between the sensory and motor neuron

Dronabinol

CB1 agonist used to treate nauasea and vomiting associated with cancer therapy

Late Stage of LTP

Can last hours, days, weeks late phase of LTP requires new protein synthesis and gene transcription synapses at which LTP has occurred undergo structural remodeling new dendritic spines grow, pre-existing spines and post synaptic densities enlarge, and single PSDs and spines can split into two functional units

DHPG-mGluR agonist mechanism

DHPG causes induction of amplitude of EPSC When DHPG is added to cerebellar purkinje fibers, the release probability decreases When CB1 receptors are inhibited , DHPG fails to have an effect

CA3 CA1 LTP mechanism

Early component of LTP is AMPA mediated, late response is NMDA mediated Glu is released from presynaptic terminal and activates AMPA receptors. Increased depol and NMDA receptors activate as well, increasing intracellular calcium The calcium activates CamKII, which phosphorylates AMPA receptors AMPA receptor phosphorylation leads to increases in channel conductance (larger postsynaptic depolarization with original stimulus Extra AMPA receptors are trapped in synapse

Cannabinoid receptors

G-protien coupled receptors; influence G-proteins involved with cAMP, Calcium and potassium currents, intracellular calcium release, and MAPK

LTD parameters

LTD induced by repetitive conjunctive stimulation of climbing fibers and parallel fibers but not by stimulation of climbing fibers or parallel fibers alone Usual sequences is climbing fiber preceded parallel fiber by 10-200msec (any stimulation within this time period will produce the same results)

NMDA dependent LTP

NT is released and interacts with AMPA receptors after enough depol of postsynaptic membrane, Mg stops blocking NMDA receptor, and it can conduct calcium current (larger sustained depol) increase in intracellular calcium causes activation of CamKII, which phosphorylates AMPA receptors This leads to a larger current and postsynaptic response with the original stimulus extra-synaptic AMPA receptors in the synapse are trapped and move to postsynaptic density, leading to even larger response

Mossy FIber-CA3 LTP

Mossy fiber release probability is usually very low after first stimulation, intracellular calcium in presynaptic terminal reminas higher than basal conditions when the second stimulus occurs, an additional increase in calcium concentration is observed in the presynaptic terminal this cases a greater number of synaptic vesicles to fuse compared to the first pulse (PPR is greater than 1)

Long Term Depression

NMDA receptor dependent, but works through phosphatases small rises in calcium activation of calcium dependent phosphatases cleave phosphate groups from target proteins loss of postsynaptic AMPA receptors

nitric oxide

NO- is a gas, it cannot be stored within cells; freely diffuses across lipid bilayer

Without oxygen and glucose, cells eventually depolarize

Normally the sodium-potassium pump maintains gradients, but in ischemic conditions ATP is depleted and the pump stops ionic balance ensues and more depolarization occurs gradients are not as different and driving force is decreased NT is released and reuptake mechanisms are compromised and start to run backwards (move glu into extracellular space

Paired Pulse Depression in ultra short term plasticity

PPR is less than 1 (more vesicle released with the first pulse) interpulse ratio usually between 20-70msec

A mechanism to uncouple NMDA channels from toxicity

PSD95 is a protein that binds the NR2B subunit and couples NMDA receptor activity to nNOS activity and NO production Tat-NR2B9C prevents this interaction and limits neuronal damage following stroke in mice (prevents NMDA-dependent increases in NO production in ischemia

Hippocampal mossy fiber LTP

Potentiation occurs even in the presence of a NMDA antagonist NMDA receptor INDEPENDENT (some forms of mossy fiber LTP do not even require activation of postsynaptic elements) NON-hebbian (sensitive to metabotropic glutamate receptors Before LTP: mossy fibers exhibit synaptic facilitation with a PPR of above 1 After LTP: mossy fibers PPR decreases, meaning the release probability increased

Withdrawal Reflexes in Aplysia (siphon gill reflex)

Single sensitizing stimulus (brief shock) leads to short term sensitization Prolonged stimulus (multiple stimuli over an hour) leads to long term sensitization (days to weeks)

Marijuana and the brain

THC mimics endogenous cannabinoids long term exposure leads to desensitization and decreased expression of CB1 receptors on the cell membrane This leads to tolerance to THC and altered CB1 function

paired pulse facilitation in ultra short term plasticity

The PPR is greater than 1 (more vesicle release with the second pulse than the first) interpulse interval usually 5-20msec (any longer and effect is not observed)

hemorrhagic stroke

a blood vessel bursts and leaks blood into the brain parts of brain not getting enough blood, other parts being flooded directly

rectifier

a molectule, channel, or system in which current flows more readily in one direction than the other OR one that changes the directionality of a current

Dogma in Neuroscience

There has been evidence of neurogenesis in humans in parts of the brain since 1960s, but scientists rejected it until the late 1990s. Even today, the idea is still challenged with some scientists saying it only occurs in children and neonates

How are endocannabinoids synthesized?

Through a process of phospholipid remodeling.

Molecular level of short term synaptic plasticity

Usually occurs with low release probability (readily releasable pool is hardly depleted) There is more NT release with the second pulse compared to the first due to an increase in extracellular calcium This is because the second pulse comes so soon that the intracellular calcium levels are still elevated

Short term sensitizations in aplysia

When the modulatory interneuron is activated, the sensory neurons is altered The AP is broadened and potassium channels are inhibited Calcium currents are increased (enhanced Ca channel activity)

Hippocampus

activated in memory tasks and damage to hipposcampus disrupts some forms of learning/memory critical for spatial learning and memory in rodents defined local circuits which can be easily visualized and maintained in slice preparations drugs/gene disruptions which alter hippocampal LTP in slices also cause alterations in spatial learning and memory

Endocannabinoid Signalling

activation of CB1 on presynaptic terminal increases potassium channel activity and reduces voltage-gated calcium channel activity This hyperpolarizes the active zone and decreases vesicle fusion Decrease probability of NT release!

non-hebbian LTP

activation of either pre or postsynaptic elements is required

Where does neurotransmitter go after it is released?

actively degraded or taken up This attentuates synaptic strength, postsynaptic strength, and removes NT from the cleft

NO and release probability

affects release probability most likely through a combination of effects including enhancing N-type calcium chennel conductance via PKG, increasing the rate of endocytosis and vesicle recycling as well as altering the balance of the readily releasable pool via PKG

Riluzole

approved for ASL treatment decreases excitability of motor neurons: inhibits TTX-sensitive sodium channels, stimulates glutamate uptake, reduces glutamate receptor activity delays ventilator use, increases life by 2-3 months

Hebbian LTP

coincident activation of both pre and post-synaptic elements is required

nitrosylation

covalent chemical modification of thiol groups on proteins to impact their activity (ex. SNARE proteins are effected by NO)

Penumbra

damage is time and location dependent immediately following an ischemic insult, there is a core of irreversible damage surrounded by an area of viable, but at risk tissue Unless blood flow is re-established soon, tissue in the penumbra will be lost and damage irreversible Site of excitotoxicity

symptoms of alzheimers disease cause

deficient synaptic activity (synapses aren't functioning properly) Two types of drugs approved to treat the cognitive symptoms of alzheimers: acetylcholinesterase inhibitors and memantine (don't stop degeneration, only help the dysfunctional synapses to work better)

decrease in synaptic strength

depression habituation (decrease in behavior)

Endocannabinoid Release

does not appear to be regulated Once it is synthesized it is released (not stored) Regulated synthesis controls it's action, not regulated release

excitotoxicity

during pathological conditions, activation of glutamate receptors can initiate neuronal death distinct from LTP/LTD mechanisms!`

Local Field Potential

electrophysiological measurements are made from extracellular environment, so the deflection looks opposite

excitotoxicity mechanism

excess calcium influx stimulates nitric oxide production (too much NO) this leads to ROS and parts of the cell get degraded

Climbing Fibers

excitatory neurons that project directly to the purkinje cells

Increases in synaptic strength

facilitation (usually short term) potentiation sensitization (increase in behavior)

how we get rid of Nitric Oxide

it is highly labile (easily broken down/changed) and essentially decomposes half life is only a few seconds

long-term depression

long lasting decrease of synaptic strength synapses becme less sensitive such that a constant level of presynaptic stimulation results in a smaller postsynaptic response

Long-term Potentiation

long lasting increase in synaptic strength synapses become more sensitive such that a constant level of presynaptic stimulation results in a larger postsynaptic response

4. Neurons are postmitotic

lost neurons can't be replaced and they can't divide There are some neuronal stem cells, but they supply new neurons to very localized areas

main processes contributing to brain's energy needs:

maintenance and restoration of ion gradients dissipated by signaling processes such as postsynaptic and action potentials, as well as uptake and recycling of NTs

Synaptic Plasticity

many mechanisms even within the same synapse, there is complexity to the process very much dependent on the paradigm

neuroprotection

mechanisms and strategies used to protect agains neuronal injury or degeneration in the central nervous system following acute disorders or as a result of chronic neurodegenerative diseases

CB2R

most present in immune system and is poorly expressed in the nervous system

NO as potent vasodilator

multiple medicines enhance nitric oxide-dependent-signaing to dilate blood vessels (viagra, nitroglycerine) increase of cytosolic calcium activates NO synthesis

nitric oxide functions

neurotransmission, cardiovascular homeostasis, immune response, angiogenesis, cell proliferation, apoptosis

CB1R

one of the most abundant GCPRs in the nervous system often localized on presynaptic nerve terminal and is a potent inhibitor of synaptic strength concentrations in the basal ganglia, cerebral cortex, hypothalamus, hippocampus, spinal cord, medulla, cerebellum

albus modification

parallel fiber activity id decreased rather than enhanced. Defined as long term depression

oxidative damage to neurons

presynaptic terminal is dependent on energy from mitochondria The mitochondria can leak electrons that attach themselves to oxygen, becoming free radicals that can be very dangerous inside the cell

retrograde signaling

process by which a compound is released by a postsynaptic dendrite or cell body, and travels "backwards" across a chemical synapse to bind to the axon terminal of a presynaptic neuron and affect its function (postsynaptic to presynaptic)

ALS

progressive degeneration of upper and lower motor neurons

purkinje cells

project axons to cerebellar nuclei

tetanus

rapidly repeated stimuli delivered such that there is no relaxation in the system high frequency/burst stimulation

mossy fibers of the cerebellum

relay to granule cells

Presyanaptic mechanism of LTP

release of NT from presynaptic cell activates presynaptic kainate receptors, which further depolarize presynaptic membrane. Also activates mGLUR receptors to activate signalling in presynaptic membrane If enough depolarization occurs, PKA is activated and proteins within synaptic vesicles involved in NT release are phosphorylated and presynaptic side of active zone (enhances ability to release NT in response to the same presynaptic stimulation (increases release probability and postsynaptic response)

two ways NO can affect ion channels

stimulation of PKG (like cAMP-dependent kinase) modification of thiol groups on proteins S-nitrosylation

Brain needs so much energy because...

synaptic potentials represent the main energetic cost related to maintenance of excitability in neurons glutamate-mediated neurotransmission is responsible for most (80%) of the energy expended in the gray matter (lots of synapses are glutamatergic)

Marr hypothesis

the gain of synaptic trnasmission at glutamatergic synapses between parallel fibers and purkinje cells changes if these synapses are repetively activated at a low rate of conjunction with climbing fibers iminging on the same purkinje cell (model of cerebellar learning)

5. Neurons are sensitive to insults

the high metabolic demand of neurons and the NS leaves them sensitive to damage (oxidative damage, death from lack of oxygen or glucose deprivation)

8. Neurons are sensitive to excitotoxicity (definition of excitotoxicity)

the pathological process by which neurons are damaged and killed by overactivations of receptors for excitatory NTs (usually glutamate) such as the NMDA or AMPA receptor

Purkinje neuron response to parallel fibers

the purkinje neuron fires consistently in and in a simple spike

Short term synaptic plasticity depression

usually occurs with high release probability The readily releasable pool is depleted after the first pulse There is still a rise in intracellular calcium; but no vesicles left to be released

Hebbian Theory

when the axon of cell "a" excites cell "b" and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that "a's" efficiency in firing "b" is increased. (LTP in response to high requency stimulation