Synaptic Unit 4

Pls let me be done with this class

HM

had a bilateral temporal lobectomy to treat seizures which resulted in anterograde amnesia; indicating that the hippocampus is necessary for the formation and consolidation of new declarative memory

entorhinal cortex

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immediately adjacent to hippocampus, main source of input into dentate gyrus

long term potentiation

long-term (hours) increase in synaptic strength; high frequency AP bursts cause a large, rapid increase in dendritic Ca2+ through NMDARs which activates calmodulin (calcium binding protein), then CaMKII (kinase), then increased AMPAR function which increases conductance

long term depression

long-term (hours) decrease in synaptic strength; induction protocols cause a small, slow increase in dendritic Ca2+ through NMDARs where depolarization has waned by the time the second stimulus comes, which activates protein phosphatases (dephosphorylation) that decrease the function of AMPARs and activates PKC that decreases AMPAR activity leading to AMPARs being removed from the plasma membrane

perforant pathway

trisynaptic loop between entorhinal cortex, dentate gyrus, CA3 pyramidal neurons, and CA1 pyramidal neurons

theta oscillations

EEG patterns found in the hippocampus

Hebbian plasticity

when neurons fire at the same time, the synapse between them becomes stronger

timing dependent plasticity

presynaptic neuron stimulated before postsynaptic leads to potentiation while post before pre leads to depression; 25ms between stimuli is the time that produces the greatest change

homosynaptic plasticity

synapse being altered is the same synapse as is being stimulated

heterosynaptic plasticity

synapse being altered is different from synapse that is being stimulated; receives many different inputs on the apical dendrite; LTP occurs closer to stimulated synapse than LTD as a result of calcium being buffered further from the synapse

apical dendrite

dendrite on top of neuron

calcium dynamics

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time and distance of calcium elevation through NMDA receptors

mGluRs

receptors that are coupled to the phosphoinositide pathway, (PLC, then DAG and IP3, then IP3R) which activates PKC which phosphorylates AMPARs and decreases activity

nitric oxide synthase

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produces membrane-soluble nitric oxide gas that diffuses to presynaptic terminal, which increases cGMP or s-nitrosylate proteins to alter function

2AG

endocannabinoid released from postsynaptic neuron that is activated by DAG and activates CB-1 receptors on the presynaptic neuron

CB-1 receptors

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metabotropic cannabinoid receptors on the presynaptic terminal which reduce neurotransmitter release and contribute to synaptic depression when activated

homeostatic plasticity

if you get unusually high amount of activity in synapse, compensatory mechanisms will bring it back down (negative feedback)

synaptic scaling

increase in “q”; postsynaptic changes in receptor expression

bicuculline

GABA receptor antagonist, blocks inhibitory neurotransmission and greatly increases activity, leads to downregulation of receptors

TTX

decreases synaptic activity, leading to increased AMPA receptor expression

neurotransmitter

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a molecule released from a neuron that transmits a signal to another cell; released into synaptic cleft, happens in very localized area, acts on nearby receptors on postsynaptic cell, underlies “fast” synaptic transmission (ionotropic)

neuromodulator

a molecule that modifies fast synaptic transmission; released into synaptic cleft through volume/paracrine transmission, effects last longer than “fast” synaptic transmission (metabotropic)

volume/paracrine transmission

diffuse release; not precise, localized release site

synaptic bouton

place along the axon that contains proteins and synaptic vesicles where you have the capability of releasing NT; much more likely to engage in volume transmission because not released into synaptic cleft

classical

type of neurotransmitter including ACh, GABA, monoamines; small molecules; uniquely synthesized at the synapse; small clear synaptic vesicles

amino acid

type of neurotransmitter including glutamate and glycine; small molecules; not uniquely synthesized at the synapse; small clear synaptic vesicles

gaseous messengers

type of neurotransmitter including nitric oxide, carbon monoxide, hydrogen sulfide; small molecules; uniquely synthesized at the synapse; no vesicles; not calcium or action potential dependent

neuropeptides

type of neurotransmitter including short peptides; large molecules; not uniquely synthesized at the synapse; large dense core vesicles

small clear synaptic vesicles

contain classical and amino acid NTs, released from active zone

large dense core vesicles

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contain neuropeptides, electron-dense, released extrasynaptically

cholinergic

every neuron that projects out of the central nervous system

acetylcholine

classical neurotransmitter used in the central and peripheral NS; released directly into a synaptic cleft or at varicosities in the PNS and from axon varicosities in the CNS; both ionotropic and metabotropic receptors but mostly metabotropic in the brain

Acetyl CoA

acetylcholine precursor produced by mitochondria from glycolysis

choline

acetylcholine precursor that comes from our diet

choline acetyltransferase (ChAT)

enzyme in reversible reaction converting acetyl coA and choline to acetylcholine and vice versa; first unique and only enzyme in the ACh synthesis pathway

high affinity choline transporter (HACU)

unique to cholinergic neurons; rate-limiting step in cholinergic synthesis; works through secondary active transport (uses sodium concentration gradient as source of energy to bring choline into cell); associated with ChAT; works when it’s on plasma membrane not vesicular membrane (needs sodium concentration to work)

vesicular acetylcholine transporter (VAChT)

uses proton gradient to pump ACh into vesicle while the vesicle also has protein pump to get protons inside vesicle, which makes inside more acidic and proton gradient powers ACh transport; works on vesicular membrane but not plasma bc it requires proton gradient between cytoplasm and vesicular interior

acetylcholinesterase

one of the fastest enzymes in the body, breaks down 5k molecules of ACh every second

diffuse modulatory systems

how modulatory neurotransmitters work through the brain

parasympathomimetic

drugs that mimic effect of activating parasympathetic nervous system

atropine

anticholinergic drug derived from *Atropa belladonna* plant that inhibits muscarinic acetylcholine receptors; dilates pupils by preventing pupil constriction from parasympathetic activation of mAChRs on the pupillary constrictor muscle

cholinesterase inhibitors

bind essentially irreversibly (covalently) to AChE and prevent its function; only way to overcome is to wait for body to make new AChE; treatments are atropine and GABA agonists

galantamine

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reversible AChE inhibitor; allosteric nAChR agonist; few side effects, can be used as an antidote to toxic cholinesterase inhibitors; combine reversible and irreversible effects and somehow it works; used to help alleviate some Alzheimer’s disease symptoms

acetylcholine hypothesis

theory that Alzheimer’s disease is a result of less ACh; supported by the facts that AD patients have reduced numbers of cholinergic neurons, blocking mAChRs in normal people causes loss of the ability to create new memories, and AD patients have reduced numbers of HACUs and ChATs and nAChRs

monoamines

dopamine (DA), norepinephrine/noradrenaline (NE), epinephrine/adrenaline (EPI), serotonin (5-HT)

noradrenergic

neuron that uses norepinephrine

adrenergic

neuron that uses norepinephrine or epinephrine

VMAT2

transports monoamines across the vesicular membrane using a proton gradient; can move monoamines from cytoplasm into vesicle and vice-versa

tyrosine hydroxylase (TH)

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converts tyrosine to L-DOPA; found in the cytoplasm, unique to catecholamine- containing neurons, first unique enzyme in catecholamine synthesis pathway (rate limiting), requires three cofactors (Fe2+, BH4, O2)

AAAD

converts L-DOPA to dopamine; located in the cytoplasm, ubiquitous enzyme; for dopaminergic neurons, the synthesis process stops here; not specific to catecholaminergic neurons; for serotonin synthesis, converts 5-HTP to serotonin in cytoplasm, then serotonin goes into synaptic vesicle through VMAT2

dopamine beta hydroxylase (DBH)

converts dopamine to norepinephrine; located inside vesicles, unique to adrenergic neurons (both NE and EPI), requires two cofactors (ascorbic acid, O2); for noradrenergic neurons, the synthesis pathway stops here

PNMT

converts norepinephrine to epinephrine; located in the cytoplasm, unique to EPI neurons; EPI is made outside the vesicle, then brought back in through VMAT2 for vesicular release

BH4

cofactor for tyrosine hydroxylase and tryptophan hydroxylase; concentration impacts rate of conversion

end product inhibition

if any of the three catecholamines are in excess, they feed back to inhibit tyrosine hydroxylase; negative feedback mechanism

monoamine oxidase

breaks down monoamines extracellularly but also associated with mitochondria so can break down NT that has been taken into cell

COMT

extracellular enzyme that breaks down catecholamines

tryptophan hydroxylase

converts tryptophan to 5-HTP in the cytoplasm with BH4 and O2 as cofactors; rate-limiting step

Raphe nuclei

source of serotonin cell bodies

locus coeruleus

source of norepinephrine cell bodies

ventral tegmental area, substantia nigra pars compacta, and infundibular nucleus

source of dopamine cell bodies

VMAT2 antagonists

prevent packaging of monoamines into vesicles, so less is released from each; have been used to treat hypertension (reduces NE) and schizophrenia (DA); side effects include Parkinsonism and depression

dopamine receptor agonists

alleviate some motor symptoms of Parkinson’s disease (L-DOPA); overdoing it can induce schizophrenic symptoms

dopamine receptor antagonists

can help treat some of the positive symptoms of schizophrenia; overdoing it can induce Parkinson’s symptom

cocaine

stimulant affecting dopaminergic transmission, so can cause a sense of energy, alertness, purposeful movement but also euphoria; blocks dopamine reuptake via DAT

amphetamine

stimulant affecting dopaminergic transmission, taken recreationally; blocks dopamine reuptake via DAT, causes DAT to pump DA molecules out of the neuron, and impairs VMAT2

MPP+

converted from MPTP by MAO; kills mitochondria when taken up by DAT, leading to advanced Parkinson’s

glutaminase

converts glutamine to glutamate

glutamate dehydrogenase

converts alpha-ketoglutarate to glutamate

aspartate aminotransferase

converts alpha-ketoglutarate and aspartate to glutamate

VGLUT

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found specifically in glutamatergic neurons; uses proton gradient (established by proton pump) to pump Glu into neurons

astrocyte

cell adjacent to synapse that can contain glutamate reuptake transporters, GABA reuptake transporters, or GLYT-1 (glycine reuptake transporters)

glutamine synthetase

converts glutamate taken into the astrocyte into glutamine, where it is transported to the presynaptic cell to be reconverted to glutamate

glutamic acid decarboxylase

converts glutamate to GABA using cofactor PLP

pyridoxine

precursor to PLP (cofactor for GABA synthesis); vitamin B6; deficiency can lead to seizures

ginkgo biloba

contains compounds that act as GABA-A and glycine receptor antagonists; reduces memory loss, dizziness, and mood disturbances; improves concentration; can lead to seizures

VIAAT

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not specific for GABA, uses proton gradient to transport GABA into vesicle

GABA-T

enzyme that breaks down GABA but is not all that critical (blocking it does not really change the IPSP)

serine trans hydroxymethyl-transferase

converts serine to glycine

 GLYT-2

glycine reuptake transporter on presynaptic cell that requires 3Na+ and 1Cl- to bring in glycine (lower affinity); not near the active zones

GLYT-1

glycine reuptake transport on adjacent astrocyte that requires 2Na+ and 1 Cl- to bring in glycine (higher affinity)

prepropeptides

precursors for neuropeptides synthesized in the ER in the soma and packaged by Golgi into large dense core vesicles which go down the axon; no action on their own, acted on in the vesicle, still need to be processed by synthetic enzymes

microtubules

these pathways traffic large dense core vesicles down from the soma to the axon terminal for release

signaling sequence

gets cleaved off of prepropeptides by synthetic enzymes to form neuropeptides

post-translational processing

after original protein synthesis in the ER is done, prepropeptides can give rise to a variety of neuropeptides

alternative splicing

splitting of exons in mRNA that code for different neuropeptides

synaptotagmin

protein with a higher affinity for calcium on large dense core vesicles than when on synaptic vesicles

neuropeptide Y

G protein coupled receptors that can have pre and postsynaptic effects; can do direct pathway and open GIRK channels but can also have an inhibitory effect on adenylyl cyclase; can affect functions such as feeding behavior, homeostasis, circadian rhythm, and stress and anxiety

nitric oxide

gaseous neurotransmitter that causes vasodilation (leading to increased blood flow); cannot be stored in the body because it is lipid-soluble and cannot be stored in vesicles because it can cross membranes and is a free radical that interacts quickly with anything it encounters; reacts with amino acids or is acted on by phosphodiesterases for action to be terminated

neuronal nitric oxide synthase

enzyme in neurons that converts arginine to citrulline using BH4 as cofactor while also producing NO from O2

endothelial NOS

form of nitric oxide synthase found in blood vessel endothelium

inducible NOS

form of nitric oxide synthase found after inflammation; not always turned on

oxidative stress

cellular damage that results from high concentrations of NO

activation of guanylyl cyclase

NO combines with iron to activate guanylyl cyclase and convert GTP to cGMP which can activate PKG

s-nitrosylation

NO reacts with cysteine residue to result in conformational change in protein leading to functional change; targets include ion channels

heme oxygenase

enzyme involved in heme catabolism that is regulated by phosphorylation of H2O and produces carbon monoxide, which does end product inhibition; activated by phosphorylation by PKC

hydrogen sulfide

gaseous neurotransmitter that enhances NMDA receptors and increases LTP induction; more likely to be neurodegenerative than neuroprotective

corelease

more than one transmitter at each synapse in the same vesicles

spatial segregation

a different transmitter at each synapse

adenosine

purine neurotransmitter converted from ATP by endoATPase and endonucleotidease