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90 Cards in this Set
- Front
- Back
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Gap Junctions |
- (electrical synapses) - channel forming structures connecting plasma membranes (pre/post-synapses) that allow direct metabolic and electrical communication between almost all cell types in the mammalian brain - gap junctions are the morphologic correlate of electrical transmission |
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Gap Junction Composition |
contain at least: - 20 connexin genes - 3 pannexin genes which code for gap junction proteins |
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Connexons |
- precisely aligned, paired channels contained by gap junctions - present in both pre/post-synaptic membranes - built from 6 presynpatic connexins aligned with 6 postsynaptic connexcins to form a pore that connects the cells (much larger than voltage-gated channels) - coded for by connexins |
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Connexins |
- a special family of ion channel proteins - make up connexons (gap junctions) |
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Functions of Gap Junctions |
- allow for direct electrical communication between cells (different connexin subunits cause different channel conductances (30pS vs. 500pS) - allow for chemical communcation between cells - metabolic coupling |
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Chemical Communication Between Cells |
- function of gap junctions - works through the transmission of small second messengers - eg. inositol triphosphate (IP3) and Calcium (Ca(2+)) |
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Metabolic coupling |
- function of gap junctions - generally allow molecules smaller than 1000 Daltons to pass through (although different connexin subunits can impart different pore sizes and charge selectivity) - large molecules (eg. nucleic acid and protein) are precluded from cytoplasmic transfer between cells |
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Upstream vs. Downstream |
- "upstream" neurons: the source of the current, the "presynaptic element" - "downstream" neuron: destination of a flow of current, the "postsynaptic element" |
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Electrical Synapses |
- physically connected at gap junction (no space) - very fast, bidirectional communication between cells - useful to generate rhythms (eg. breathing) and oscillations (eg. interneuron networks) - protein interactions draw synapses together for transfer (link activity in 1:1 ratio) |
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Electrical Transfer of Information |
- direct transfer of info/impulse in both depolarizing and hyperpolarizing currents - postsynaptic response proportional to change in potential in presynaptic cell |
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Chemical Synapses |
- more abundant (and important) - distinct synapses (synaptic clefts) - translates: electrical signal -> chemical signal -> electrical signal - neurotransmitters packaged/stored in vesicles |
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Regulation of Chemical Synapses |
- regulated by enzymes (small-molecule neurotransmitters) |
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Most Common Type of Chemical Synaptic Contacts |
the most common type is the contact between an axon terminal and a dendritic, somatic, or axonal domain |
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Electrical vs. Chemical Synapses: Distance Between Pre/Post-Synaptic Cell Membranes |
Electrical: 3.5 nm (very close)
Chemical: 20-40 nm (further) |
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Electrical vs. Chemical Synapses: Cytoplasmic Continuity Between Pre/Post-Synaptic Cells |
Electrical: yes
Chemical: no |
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Electrical vs. Chemical Synapses: Ultrastructural Components |
Electrical: gap-junction channels (connexons)
Chemical: - presynaptic vesicles and active zones - postsynaptic receptors |
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Electrical vs. Chemical Synapses: Agent of Transmission |
Electrical: ion current
Chemical: chemical transmitter |
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Electrical vs. Chemical Synapses: Synaptic Delay |
Electrical: virtually absent
Chemical: significant, at least 0.3 ms, usually 105 ms or longer |
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Electrical vs. Chemical Synapses: Direction of Transmission |
Electrical: usually bidirectional
Chemical: unidirectional |
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Criteria that Define Neurotransmitters |
1. the substance must be present within the presynaptic neuron 2. the substance must be released in response to presynaptic depolarization and the release must be Ca(2+)-dependent 3. Specific receptors for the substance must exist on the postsynaptic cell |
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Neurotransmitters Must: |
be packaged and released in vesicles in response to presynaptic depolarization |
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Problems with Neurotransmitter Criteria |
1. the substance must be present within the presynaptic neuron - transmitters like glutamate, glycine, and aspartate also have other functions in cellular metabolism and/or function as precursor for other transmitters (eg. dopamine) - therefore, their presence is not sufficient to establish them as neurotransmitters |
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(2) Major Classes of Neurotransmitters |
- "Classical" neurotransmitters (small molecules) - Neuropeptides |
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"Classical" Neurotransmitters |
- one of the major classes of neurotransmitter - small molecules - local synthesis in the presynaptic terminal - synthesizing enzymes comes from nucleus via slow axonal transport - first to be released - easily replenishable - small, clear core vesicles |
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Neuropeptides |
- one of the major classes of neurotransmitter - synthesis in the soma (nucleus, rough ER [pre-propeptides], and golgi apparatus [propeptides]) - complete vesicles reach terminal via fast axonal transport through microtubules where they can be moved to the active zone and releasted - not easily replenishable - large, dense core vesicles |
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Slow Axonal Transport |
- used by "classical" neurotransmitters - 0.5 to 10 mm per day - always anterograde |
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Fast Axonal Transport |
- used by neuropeptides - 20 to 400 mm per day - anterograde for neuropeptides (but can be retrograde for transport of other things) |
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Example of "Classical" Neurotransmitter Synthesis |
(within the presynaptic terminal) GABA and glutamate synthesis: - astrocytes regulate neurotransmitter synthesis (take up/recycle GABA and glutamate that are released at synaptic clefts - astrocytes then release glutamine which can be used by neurons to make new glutamate/GABA |
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Co-Release of Small Molecule Neurotransmitters and Neuropeptides |
- neuropeptides: requires high-frequency stimulation (importance of Ca(2+) levels in the presynaptic terminal) - small molecule neurotransmitters: low-frequency stimulation is preferential, but can be released with high-frequency too |
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The Neuromuscular Junction (NMJ) |
- large postsynaptic cell or "end plate" (filled with acetocholine which acts on nicotinic receptors) - one axon (but about 100 synapses) per muscle cell - highly reliable (most presynaptic APs lead to postsynaptic APs) - chemical signaling is simple (only one type of ion channel) |
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Neuromuscular Junction (NMJ) Activity is Mediated by: |
acetocholine |
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Synaptic Events and Initiation of APs at the Neuromuscular Junction (NMJ) |
1. ACh binding at transmitter-gated channels 2. Channel opening 3. Na(+) inflow/K(+) outflow 4. Depolarization (end-plate potential) 5. Opening of voltage-gated Na(+) channels 6. Na(+) inflow 7. Depolarization 8. Action Potential |
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Synaptic Events at the NMJ |
- stimulation of motor fiber generates a synaptic potential in the post synaptic muscle cell - this causes and End Plate Potential (EPP) of about 40 - 50mV in amplitude - however, very small (miniature) potential (~1mV) occur even in the absence of stimulation (Miniature End Plate Potentials (MEPPs)) |
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End Plate Potential (EPP) |
- a transient depolarization in the membrane potential of the postsynaptic muscle fiber from an AP in a presynaptic motor neuron - triggers muscle to contract - multiples of miniature EPPs (MEPPs) - APs synchronize the release of many neurtransmitter quanta - minimum EPP increased with Ca(2+) |
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Miniature End Plate Potential (MEPP) |
- spontaneous neurotransmitter release which occurs in quantal packets - have the same shape as EPPs but are much smaller in amplitude - always the same size (vesicles are the same and contain the same amounts of neurotransmitters) - occurs even in the absence of stimulation |
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End Plate Potentials (EPPs) Amplitude vs. Miniature End Plate Potentials (MEPPs) |
EPPs: ~40 to 50mV amplitude
MEPPs: ~1mV amplitude |
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Key Variable that Characterize Quantal (Vesicular) Release (Katz's Variables) |
- the number of release sites (N) - the probability of quantal release (p) - the size of the quantal response (q) |
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Quantal Analysis |
extracting the best-fitting values of the N, p, and q variables from the distribution of postsynaptic response amplitudes fitted to a binominal distribution |
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Morphological Correlates of Katz's Variables |
- the number of release sites (N) -> number of active zones/synapses - the probability of quantal release (p) -> number of docked vesicles - the size of the quantal response (q) -> single vesicle and/or the response to a single vesicle (receptor sensitivity) |
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Docked Vesicles |
- vesicles attached to the membrane for release - the morphological correlate of the Katz variable: probability of quantal release (p) |
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Size of Quantal Response (q) |
- one of Katz's variables - response = number of neurotransmitters on postsynaptic site - only number of postsynaptic potentials can be changed |
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Plasticity of the Size of the Quantal Response (q) |
more post synaptic receptors |
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Calcium |
- required for neurotransmitter release (influences the probability of release) - presynaptic APs open voltage-gated Ca(2+) channels - Ca(2+) allows vesicles to fuse with membrane - steep, non-linear dependence on Ca(2+): 2x increase in Ca(2+) increases neurotransmitter release 16x (little Ca(2+) = big response/release) |
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Where Calcium is Found in a Neuron |
- not distributed through axon - cumulate at presynaptic synapses |
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Calcium Buffer |
- BAPTA buffers Ca(2+) - prevents post-synaptic response (which shows Ca(2+) dependence) |
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The Active Zone |
- APs trigger Ca(2+) influx into presynaptic terminal via voltage-gated Ca(2+) channels - very large Ca(2+) fluxes because of their accumulation in this area, very steep concentration gradient (10x larger than elsewhere; concentration can rise 1000x) - Ca(2+) sensor (synaptotagmin) on synaptic vesicles |
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Synaptotagmin |
- "calcium sensor" (Key protein -> C2 domain) - binding of 4 Ca(2+) is needed to trigger release - 2x increase in Ca(2+) can increase synaptic release 16x - low-afinity binding (50-100 μM) compared to that of many other Ca(2+) binding proteins (~1 μM) (but can still sense) allowing rapid dissociation/termination when Ca(2+) levels fall |
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Functions of Synaptogemin |
- modulates number of early synaptic vesicle docking to the presynaptic membrane via interactions with β-neurexin or SNAP-25 (for release through its interactions) - late steps of Ca(2+) evoke synaptic vesicle fusion with the presynaptic membrane - width (shape) of AP controls neurotransmitter release |
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Width of Action Potential on Neurotransmitter Release |
shape of AP is very important: controls output properties of the response
- narrow AP -> less neurotransmitter release (many Ca(2+) channels open, but not a whole lot) - wide AP -> more neurotransmitter release (Ca(2+) channels stay open for longer) |
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Ca(2+) Affects... |
(the probability of release, not the quantal size) - At the NMJ APs normally trigger release of ~150 quanta, each generating a synaptic potential of 0.5 mV - normal spontaneous release level is 1 quanta per second (Ca(2+) influx increases probability of release 100,000x) - at central synapses, an AP normally triggers the release of only 1-10 quanta |
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Reed Heuser |
- looked at frog NMJ and found administration of 4-AP drug blocks K(+) channels which increases duration of an AP (more quanta released) and amount of Ca(2+) that can enter - used horseradish peroxidase (HRP) to see electron microscopy better - correlates perfectly with the number of fused vesicles counted in the electron microscopy |
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The Synaptic Vesicle Cycle |
1. transmitter trafficed/moved to be loaded at synaptic cleft (along microtubules) 2. transmitter loaded into vesicles at synapse 3. vesicles docked (requires precise orientation) 4. priming (assembly/orienting) 5. fusion (Ca(2+)) channels open 6. endocytosis 7. transmitter uptake/breakdown (or endosomal fusion and budding) |
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Vesicle Fusion |
- vesicle fusion of a transport vesicle with its target - involves 2 types of events - explained by SNARE hypothesis |
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(2) Events Involved in Vesicle Fusion |
1. the vesicle must recognize the correct target membrane 2. the vesicle and its target membrane must fuse (to deliver to either the target organelle within the cell or the synaptic cleft between the cells - exocytosis) |
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Exocytosis |
- release of transmitters into the synaptic cleft between two cells - used for communication |
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SNARE Hypothesis |
- explanation for vesicle fusion (exocytosis) - fusion occurs via the interaction between specific pairs of transmembrane proteins called "SNAREs" on the vesicle (v-SNAREs) and the target membrane (t-SNAREs) |
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Functions of Proteins Involved in Synaptic Release |
- restrain vesicles - target vesicles to active zone - allow fusion/exocytosis - retrieve fused membrane (recycling) |
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SNAP Receptors |
- group of proteins that promote fusion of the vesicle with the presynaptic membrane - includes Synaptobrevin, Syntaxin and SNAP-25, and Synaptotagmin |
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Synapsins |
- cytoskeletal filaments which dock (tether) transmitter to membrane - regulated by cAMP-dependent kinase and Ca(2+)/Calmodulin-dependent kinase - phosphorylation frees vesicles to move (very important for process) |
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CaMKII |
- phosphorylates Synapsin to mobilize the Reserve pool |
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Proteins Involved in Exocytosis (SNARE Hypothesis) |
- V-SNAREs (and Synaptobrevin - "vamp") - T-SNAREs (and Syntaxin/SNAP25) - Synaptotagmin - munc-18 - Neurexins - NSF (N-ethylmaleimide sensitive factor) and α-SNAP (soluble NSF attachment protein) |
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munc-18 |
- protein involved in exocytosis (SNARE hypothesis) binds with syntaxin to inhibit SNARE complex formation |
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Neurexins |
- protein involve din exocytosis (SNARE hypothesis) - interacts with synaptotagmin (leading to fusion after forming) |
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NSF and α-SNAP |
- N-ethylmaleimide sensitive factor (NSF) and soluble NSF attachment protein (α-SNAP) - responsible for priming (binds SNARE and utilizes ATP to break apart complexes after fusion) |
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Main Purpose of Priming |
to organize the SNARE proteins into correct conformation for membrane fusion |
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Importance of Phosphorylation |
- synapsins - frees vesicles to move in exocytosis process |
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Synaptobrevin |
- "VAMP" - SNAP Receptor protein - sits in the vesicle membrane (V-SNARE or "vesicle-SNARE") - involved in exocytosis |
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Syntaxin and SNAP-25 |
- SNAP Receptor proteins - are anchored in the presynaptic membrane (T-SNAREs) - two most well understand of the proteins |
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Synaptotagmin |
- SNAP Receptor protein - not a SNARE but needed for complex - Has two C2 domains that are related to regulatory domains on PKC (bind phospholipids in Ca(2+)-dependent manner) |
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Exocytosis Process According to SNARE Hypothesis |
1. vesicle docks 2. SNARE complexes form to pull membranes together 3. entering Ca(2+) binds to synaptotagmin 4. Ca(2+)-bound synaptotagmin catalyzes membrane fusion |
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Rab Proteins |
members of the Ras superfamily of G-proteins - not well known/understood - involved in the transport of vesicles |
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Rab Protein Involvement in Vesicle Transport |
- over 60 different Rab proteins are involved - regulate many steps of membrane traffic (including vesicle formation, vesicle movement along actin and tubulin networks, and vesicle fusion) - mark transport vesicles - interact with V-SNAREs to initiate fusion |
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Synaptotagmin Functions |
- Ca(2+) sensor (releases clamp on or facilitates release - the final push for membrane fusion) - may also aid in recycling by binding to clathrin - binds phospholipids in a Ca(2+)-dependent manner (on C2 domains) - picks up change (increase in Ca(2+)) in membrane and causes conformational changes in proteins |
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(3) Different Modes of Exocytosis |
- Classical exocytosis - Kiss and Run exocytosis - Bulk endocytosis |
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Classical Exocytosis |
- a mode of exocytosis - involves the clathrin-coated pits - clathrin triskelions coat the presynaptic neuronal membrane and draw the membrane out - the pits eventually bud and are pinched off by dynamin |
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Kiss-and-Run Exocytosis |
- a mode of exocytosis - does not involve clathrin as the vesicle only briefly makes contact with the membrane to release the NT it contains - fully fuses but doesn't fully expand vesicle - is not completely absorbed by the neuronal membrane |
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Bulk Endocytosis |
- least understood mode of exocytosis - takes back vesicle for recycling (1st point in cycle when it differs from the other 2 modes) - involves extra membrane budding from the presynaptic neuron to form a vacuole-like structure (larger than a vesicle) - research indicates it is found after high-frequency, high-activity firing |
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Endocytosis Cycle |
1. coats vesicle with clathrin triskelion (forming a coated pit) 2. buds out 3. dynamin pinches off the coated pit (vesicle) |
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Clathrin Function |
- endocytosis - "clathrin triskelion" - coats vesicles to form coated pits |
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Dynamin Function |
- endocytosis - pinches off clathrin-coated pit (vesicle) which has budded out of the membrane (frees pit to travel) |
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Post-Synaptic Neurotransmitter Receptors |
- ionotropic (direct gating) - metabotropic (indirect gating - used G-protein and 2nd messenger) |
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Ionotropic Receptors |
- or ligand-gated - directly causes conformational changes in channels (direct active process) |
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Metabotropic Receptors |
- not directly connected to channel (indirect active process) - uses G-proteins |
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Post-Synaptic Potentials (PSPs) |
- response on post-synaptic cell - either EPSP or IPSP - has direction determined by ionic identity and the equilibrium or reversal potential |
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(2) Determinants for Post-Synaptic Potential (PSP) Direction |
1. the ionic identity 2. the equilibrium or reversal potential (and EPSP reversal potential is more positive than the AP threshold, while an IPSP reversal potential is more negative than the AP threshold) |
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Excitatory Input (EPSPs) |
- usually glutamate - permeable to both Na(+) and K(+) - reversal potential is more positive than the AP threshold |
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Inhibitory Input (IPSPs) |
- usually GABA - permeable to Cl(-) - reversal potential is more negative than the AP threshold |
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Synaptic Inhibition |
- reduces the probability of firing an action potential (an active inhibitory synapse takes away from an excitatory synapse) - GABAA or glycine receptors open Cl(-) channels, resulting in an inward flow of negatively charged Cl(-) ions and leading to hyperpolarization - a synaptic potential can be depolarizing and yet inhibitory |
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How a Synaptic Potential Can Be Depolarizing, Yet Inhibitory |
- synaptic inhibition - depolarizing synaptic potentials can inhibit neurons as long as the ECl(-) is more hyperpolarized (negative) than the action potential threshold (shunting inhibition) |
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Shunting Inhibition |
- synaptic inhibition - increasing "resting" conductance by opening Cl(-) channels (ie. reduces resistance) - based on Ohm's law (V=IR) (takes more current (I) to change the membrane potential (V) when resistance is lower) - If ECl(-) = RMP, opening Cl(-) channels won't hyperpolarize the cell, yet acts inhibitory on simultaneous EPSPs |
