Term
| Describe the basic structure of the NMJ |
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Definition
1) Single motoneuron (enveloped by Schwann cell) per muscle, with multiple fibers in that muscle being innervated by the same neuron.
2) Synaptic cleft is 60 nm separation between neuron and muscle fiber and single action potential always elicits a post-synaptic response
3) Ach transmission with AchE bound to basilar membrane prevents over-contraction. |
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Term
| What are the 9 important steps of Quantal (vesicular) neurotransmitter release? |
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Definition
Total cycle takes 1 min
Docking, Priming, Fusion, Endocytosis, Translocation, Endosome fusion, Budding, Transmitter Uptake and Translocation
1) Docking at "active zones" opposite to synaptic cleft (inhibited by clostridial toxins)
2) Priming (ATP-dependent maturation of vesicles for Ca-mediated exocytosis)
3) Fusion- rapid event (<300us) that depends on voltage-gated calcium channels, which mediate interactions between synaptotagmin and syntaxin
** alfa-latroctoxin venom from black widow triggers calcium-indenpendent fusion**
4) Endocytosis (internalization in clathrin-coated pits (1-5s)
5) Translocation (coated vesicles shed their coats, acidify and move to interior for recycling).
6) Endosome fusion with recycling vesicles
7) Budding (regeneration of synaptic vesicles from endosome)
8) Neurotransmitter uptake via active transport (proton-pump EC gradient)
9) Translocation to active zone (cytoskeleton or diffusion) |
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Term
What do each of the following toxins do?
1) Conotoxin (snail)/agatoxin (bee)
2) Clostridium botulinum
3) Alfa-latroctoxin (black widow) |
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Definition
1) blocks neuronal calcium channels and prevents NT release
2) cleave docking proteins (syntaxin and synaptotagmin) at synaptic cleft
3) triggers Ca-independent vesicle fusion |
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Term
| What are the 2 major postsynaptic mechanisms of synaptic transmission with neurotransmitters? |
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Definition
1) Ligand-gated membrane ion channels (ionotropic)
- opening causes influx or efflux of single (glycine) or multiple (Ach) ions
- Fast, short-lasting responses
2) G-protein coupled (metabotropic)
- binding activates intracellular transducer, which affects conductance of membrane ion channels or induces other cascades |
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Term
| What are the 5 criteria that make a Neurotransmitter a neurotransmitter? |
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Definition
1) Synthesis in pre-synaptic cell
2) Release from pre-synaptic terminal in calcium-dependent and activity-dependent manner.
3) Identity of origin (when applied exogenously, the compound should mimic the endogenous effects
4) Pharmacological identity through drug-blocking
5) Termination of action |
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Term
| What is the difference between small-molecule neurotransmitters and neuroactive peptides? |
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Definition
1) Small-molecule transmitters such as biogenic amines and AAs are contained in small, lucent vesicles and can also be co-released with neuropeptides
2) Neuroactive peptides are contained in large, dense-core synaptic vesicles. |
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Term
| Where and how is Ach synthesized? How is this process regulated? |
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Definition
1) In the cytoplasm of neurons in CNS and PNS
2) Choline acetyl transferase (ChAT) mechanism where acetyl-CoA and choline become Ach and CoA
- Acetyl-CoA made in mitochondria in terminals
- Choline not made in brain, but transported in blood in both free form and as phosphatidyl choline, and taken up by receptors in presynaptic terminal.
-ChAT is made in terminal and axons, and transported to soma
3) Regulated by CHOLINE UPTAKE |
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Term
| What are the major types of AchRs and how do they work? |
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Definition
1) Nicotinic.
- Multimeric ionic pore (2a3b) permeable to Na, K and Ca
- Bocked by neuronal bungarotoxin
- Similar to those found in muscle, but muscle is 2a1b1y1d and is blocked by alpha-bungarotoxin
2) Muscarinic
- Second messenger system (GPCR) in brain, smoth muscle, heart and secretory glands
- IP3 and cAMP mediated ion-channel opening
- blocked by atropine and scopolamine |
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Term
How do each of the following compounds affect neuronal signaling?
1) Alpha-bungarotoxin
2) Neuro-bungarotoxin
3) Atropine
4) Scopolamine
5) Alfa-latroctoxin (black widow)
6) Fasciculin
7) Sarin gas |
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Definition
1) blocks Nicotinic AchR (muscle)
2) blocks Nicotinic AchR (neurons)
3 and 4) Block muscarinic AchR
5) Calcium-independent NT vesicle fusion
6) AchE inhibitor from green mamba snake
7) Irreversible AchE inhibitor |
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Term
| How is Ach signaling terminated? |
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Definition
1) AChE (extracellular protein) associated with cell membrane breaks down ACh into choline and acetic acid.
2) Choline is recycled by uptake into presynaptic neuron
3) Carbamates (reversible), Fasciculin (green mamba snake), Insecticides and Sarin gas (irreversible) are all inhibitors. Maybe use in AD because of cholinergic drop? |
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Term
| What central neurological pathway is degenerated in AD? |
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Definition
| Neurons in the Nucleus Basalis of Meynert, which is located in the basal forebrain and is the primary cholinergic input for the cerebral cortex. |
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Term
| What are the 3 major Catecholamines and where/how are they synthesized? |
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Definition
All derived from Tyrosine, which is taken up from blood via active transport. Dopamine is taken up into synaptic vesicles via vesicular monoamine transporters.
1) Dopamine (CNS)- Tyr to L-Dopa via TH (RATE LIMITING) and L-Dopa to dopamine via Dopamine decarboxylase
2) NE (post-ganglionic in PNS and in CNS) - Dopamine to NE via Dopamine-beta-hydroxylase
3) Epinephrine (hormone released from adrenal medulla and small amounts in brain stem)
- NE to Epinephrine via P,N-Methyl transferase |
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Term
Explain how each of the following enzymes acts in Catecholamine synthesis.
1) Tyrosine Hydroxylase
2) Dopa Decarboxylase
3) Dopamine-beta-Hydroxylase
4) PNMT |
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Definition
1) RLS in synthesis (Tyrosine to L-Dopa) found in cytosol of catecholamine-containing neurons and adrenal medulla
2) Cytoplasmic enzyme found in all catecholamine-producing neurons with B6 cofactor (L-Dopa to Dopamine).
3) Ascorbic acid cofactor and only found INSIDE synaptic vesicles of catecholaminergic nerve terminals that utilize NE (Dopamine to NE)
4) Cytosolic enzyme largely restricted to Chromaffin cells adrenal medulla (NE to Epinephrine, ATP-dependent, proton-driven storage in granules) |
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Term
| What are the major Catecholaminergic receptors? |
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Definition
1) Dopamine
- D1-like (D1 and D5) found in corpus striatum and activate AC, leading to increase in cAMP
- D2-like (D2-D4) inhibit AC and decrease cAMP: found in striatum, pituitary and cortex. Stimulation activates K channels and/or inactivates Ca-channels.
2) Epi and NE
- B1: linked to stimulation of AC and found in cortex
- a1: linked to phosphoinositide turnover and increase intracellular calcium (found post-synaptically on blood vessels and peripheral tissues).
- a2: linked to inhibition of cAMP; present at presynaptic terminal for decreased NT release. |
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Term
| How do the anti-psychotic drugs fluphenazine (Prolixin), chlorpromazine (Thorazine) and Haloperidol (Haldol) treat Schizophrenia? |
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Definition
Potent D2 antagonists (inhibitory dopamine receptors)
Schizophrenia has been linked to over-active D2 receptors |
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Term
| How is the action of catecholamines terminated? |
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Definition
Slow compared to AChE
1) MAO and Catechol-O-MT break down catecholamines.
- MAOIs like deprenil are used to treat depression and PD
2) ATP- and Na-dependent reuptake (inhibited by cocaine, amphetamines and tricyclics).
3) Rapid, spontaneous chemical oxidation to dopachrome, which polymerizes to neuromelanin, which deposits in catecholaminergic containing neurons (SN and locus correlius look black!) |
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Term
| What are the major Catecholaminergic pathways in the CNS? |
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Definition
1) DA
- Nigrostriatal (zona compacta of SN to caudate and putamen of striatum)
- Mesocortical/"mesolimbic" (project diffusely to the frontal and cingulate cortex and overactive in Schizophrenia).
- Tuberoinfundibular
2) NE
- Locus ceruleus in caudal pons projects to spinal cord and cerebellum, as well as to the hippocampus and cortex via the medial forebrain bundle
3) Adrenergic
- Some cells found in brain stem with NE neurons, but with PNMT and projecting to hypothalamus. |
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Term
| Where and how is 5-HT synthesized? How is this process regulated? |
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Definition
Released from aggregating platelets and NT in mammalian brain.
1) Synthesized in cytoplasm of neurons in Raphe nucleus and Pineal gland (then made into melatonin) from Tryptophan
- Tryptophan enters neurons via active transport (inhibited by Phe from Nutrasweeet!)
- Hydroxylated by tryptophan hydroxylase to 5-Hydroxy-tryptophan (RLS)
- Converted to 5-hydroxytryptamine by L-amino acid decarboxylase. |
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Term
| How do 5-HT receptors work? |
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Definition
Second Messenger Systems EXCEPT 5-HT3, which is directly coupled to cation-selective channel
- When receptor binds 5-HT, AC leads to cAMP synthesis, PKA activation and K channel phosphorylation. Closure of the K channel leads to slow depolarization and action potential generation
- LSD is receptor agonist
- MDMA increases release, as well as DA and NE. |
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Term
| How is the action of 5-HT terminated? |
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Definition
1) MAO-mediated breakdown
2) Re-uptake via SERT (primary mechanism), which is the primary target of fluoxetine (Prozac) |
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Term
| What central serotonergic pathways are found in mammals? |
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Definition
1) Raphe nuclei in midline of pons and upper brain-stem send axons to striatum, cortex, cerebellum and thalamus.
- activity is correlated with behavioral state (high during waking and low during REM)
- projections to dorsal horn control pain perception |
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Term
| Which neurological diseases are associated with GABA signaling? |
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Definition
| Huntington's Chorea, Parkinson's, Epilepsy |
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Term
| How/Where is GABA synthesized? |
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Definition
1) Synthesized in terminal's cytosol and transplorted into vesicles for storage and release
2) Glutamate acid decarboxylase (GAD) converts glutamate to GABA and GABA transaminase (GABA-T) converts aKG to GABA |
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Term
| What are the major types of GABA receptors and drugs that act on them? |
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Definition
1) GABA-A contains ion channel selective for Cl- ions (Analagous to nAChR but with a single ion)
- binds Benzodiazepines such as Diazepam (Valium) and anxyolitic triazolam (Halcion), which facilitate GABA-binding.
- Barbiturates, Anticonvuslans (Valproic acid) and Steroid Anesthetics act on distinct sites but have similar effects.
2) GABA-B utilized GPCR, AC mechanisms leading to activation or inactivation of ion chennels through cAMP (analogous to m-AChR) |
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Term
| How is GABA signaling terminated? |
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Definition
MOST PREVALENT in brain and found EVERYWHERE.
-Once released, GABA is actively taken up by pre-synaptic terminal and by neighboring astrocytes.
- Can be recycled and re-released or trans-aminated to succinic acid for the Krebs Cycle. |
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Term
| Where/How is Glycine Synthesized? |
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Definition
Non-essential AA derived from Serine in the brain via serine hyroxymethyltransferase (SHMT)
**not carried in blood to brain** |
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Term
| What are the major types of Glycine receptors and drugs that act on them? |
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Definition
Located in spinal cord and brain stem (perhaps in the neocortex and hippocampus as well)
- Directly coupled to chloride-selective ion channel.
- Strychnine blocks inhibitory glycine receptors
- Taurine and B-alanine activate receptor
- NMDARs in forebrain and cerebellum have glycine-sensitive, strychnine-insensitive sites which require glycine for glutamate-mediated activation! |
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Term
| How does Glycine signaling act in the forebrain and cerebellum? |
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Definition
| There are NMDARs with glycine-sensitive, strychnine-insensitive sites, which require glycine-binding for subsequence glutamate binding and activation. |
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Term
| How is Glycine signaling terminated? |
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Definition
1) Removed by active, Na-dependent glycine transport system
- GLYT1 in neurons and glia
- GLYT2 only in axon terminals (termination at synaptic cleft) |
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Term
| What are the major Glycinergic pathways? |
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Definition
1) Renshaw cell inhibition of motoneurons in recurrent inhibitory pathway of the spinal chord
2) Brain-stem regions and in retina. |
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Term
| Where/How is Glutamate Synthesized? |
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Definition
1) Most plentiful AA (non-essential) in adult CNS that does not cross BBB (no blood supply)
2) Derived from Glutamine (Glutaminase) and AKG (Glutamic acid DH) |
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Term
| What are the major types of Glutamate receptors and drugs that act on them? |
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Definition
3 Ionotropic types (directly coupled to ion channel): NMDA, AMPA and Kainate
1 Metabotropic:
1) Kainate and AMPA mediate fast synaptic potentials through Na and K permeability (NBQX)
2) NMDA is permeable to Na, K and Ca, slower than Kainate and AMPA receptors, and has a Mg block during hyper-polarization (APV, PCP and Ketamine)
- Glutamate-activation is dependent upon Glycine binding. |
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Term
| How is Glutamate signaling terminated? |
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Definition
| Uptake system primarily through Astrocytes, but also pre-synaptic terminal. |
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Term
| Where/How are Neuropeptides synthesized? |
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Definition
1) Peptides or pro-peptides are synthesized in soma, packed into vesicles in smooth ER and axonally transported to synaptic cleft.
** Alternate cleavage of pro-peptide generates related peptides**
** Released in Bursts and can modify the action of classical co-transmitters** |
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Term
What is the function of each of the following Neuroactive peptides?
1) Thyrotrophin-released hormone (TRH)
2) Oxytocin and Vasopressin
3) LHRH
4) Brain-gut peptides
5) Opioid |
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Definition
1) Hypothalamic tripeptide that stimulates adenohypophyseal cells to secrete TSH.
2) Synthesized in Supraoptic and Paraventricular nuclei of hypothalamus. Released in Neurohypophysis into the bloodstream. Oxytocin (uterine contractions) and Vasopressin (water reabsorption in distal tubule)
3) Produced in hypothalamus to stimulate LH from the adenohypohysis, leading to slow synaptic potentials in sympathetic ganglia.
4) Cell-cell messengers in GI and CNS such as Somatostatin in the hypothalamus, DRG, amygdala and neocortex (depressent), CCK in some neurons and Vasoactive intestinal peptide (VIP).
5) Binds opioid receptors (GPCRs) and lower pain. |
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Term
| What are 2 examples of GPCR systems in neurons? |
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Definition
1) LHRH system (also have input from Ach cels for rapid potential changes through nAchR) with closure of K channel that is open at rest.
2) 5-HT system (GPCR system leading to K channel closure) |
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Term
| What are the major ligand-gated channels in the CNS? |
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Definition
1) Ach nicotinic R
2) GABA-A (IPSC)
3) Glycine inhibitory, strychnine-sensitive (IPSC)
4) AMPA, kainate and NMDA (EPSC) |
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Term
| How does an EPSP influence the likelihood that a postsynaptic neuron will fire? |
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Definition
- Simultaneous permeability changes in sodium and potassium channels due to transmitter binding (gNa is NOT regenerative in this case and it is NOT voltage-gated)
-These transmitter-gated ion channels are different from voltage-gated channels
- Since gNa and gK increase simultaneously, reversal potential for excitation (Eepsp) is 0mV or somewhere between Ena (+50mV) and Ek (-70mV). SO, EPSP drives membrane potential from resting value towards Eepsp.
- EPSP increases membrane resistance and therefore increases efficacy of excitatory signal generation. |
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Term
| How does an IPSP influence the likelihood that a postsynaptic neuron will fire? |
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Definition
- At inhibitory synapses, binding of NT leads to increase in gCl-, and since resting potential is greater than the equilibrium potential for chloride (ECl), opening of these channels will cause chloride influx and membrane hyperpolarization.
- This hyperpolarization decreases membrane resistance and decreases synaptic membrane potential changes created by a given synaptic current (i.e. Excitatory currents are less effective!). |
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Term
| What are the 3 major ways by which Synaptic Efficacy is modulated? |
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Definition
Can be pre- and post-synaptic plasticity
1) Presynaptic inhibition (GABA-A/Cl channel or GABA-B/Calcium channel)
- occurs when axoaxonic synapses release GABA onto presynaptic terminal, decreasing the amount of transmitter being released
- occurs either through GABA-A receptors coupled to a chloride channel which decreases membrane resistance or through activation of GABA-B receptor, which inhibits voltage-gated calcium channels through second messenger systems involving PKC.
2) Facilitation (pre-synaptic calcium influx from buffer saturation)
- Intense stimulation (tetanic stimulation) leads to enhanced response to subsequent single stimulus (PTP)
- PTP lasts seconds to minutes and has pre-synaptic mechanism involving increases in calcium due to transient saturation of calcium buggering systems.
3) LTP
- Mediated by NMDARs and post-synapstic calcium influx at central synapses in CA1 of hippocampus
- NMDARs are "coincidence detectors". During intense stimulation such as tetanus, EPSPs begin to ride on each other (temporal summation), such that the membrane potential becomes sufficiently depolarized to release Mg block, allowing calcium influx and non-NMDA receptor modification for EPSP enhancement. |
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Term
| How does LTP work at central synapses of CA1 in the hippocampus? |
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Definition
- Mediated by NMDARs and post-synapstic calcium influx
- NMDARs are "coincidence detectors". During intense stimulation such as tetanus, EPSPs begin to ride on each other (temporal summation), such that the membrane potential becomes sufficiently depolarized to release Mg block, allowing calcium influx and non-NMDA receptor modification for EPSP enhancement. |
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