Neuroscience/Objectives/Lecture 8

From PhysioWiki

Synaptic physiology

CONTRAST the function of the neuromuscular junction to that of the synapses in the CNS.

COMPARE chemical to electrical synapses in the CNS.

CONTRAST EPSPs and IPSPs and their relationship to action potential generation.

EPSPs and IPSPs are excitatory and inhibitory postsynaptic potentials, respectively. They result from excitatory or inhibitory postsynaptic currents (EPSCs and IPSCs) that result from stimulating the postsynaptic cell. If the current is net-depolarizing, then the result will be an EPSP; if it is net-hyperpolarizing, then the result will be an IPSP.

EPSPs (and IPSPs) are not action potentials, though they do contribute to the generation of action potentials. EPSPs make action potentials more likely, while IPSPs make them less likely. Spatial and temporal summation of excitatory and inhibitory PSPs determine whether an action potential will be initiated. If the sum of PSPs is sufficiently depolarizing, then enough postsynaptic sodium channels will be open (i.e. enough to outnumber the potassium channels) to generate an action potential.

COMPARE temporal with spatial summation.

Temporal summation is a consequence of the time it takes to charge and discharge the neuronal cell membrane, which is determined by the time constant, τ. Larger time constants result in greater discharge times, so that the membrane is able to retain its charge for a greater period of time. The longer a patch of membrane holds its charge, the longer the membrane can separate charge, and the longer a membrane will remain depolarized after receiving a net-depolarizing stimulus. When an already-depolarized patch of membrane is stimulated with a subsequent EPSP, then the membrane will be further depolarized. This is temporal summation.

Spatial summation is related to the space constant, λ, and results from the attenuation of voltage with increasing distance. If a graded potential begins at point A and ends at point B, the magnitude potential at B will be less than that at A because of the attenuation of the signal over the distance between A and B. The longer the distance (and the longer the space constant), the greater the attenuation. When an EPSP is generated at a patch of membrane adjacent to an already-depolarized patch of membrane (i.e. close enough so that the signal has not attenuated between the two membrane patches), then the resulting EPSP will be the sum of the EPSPs generated. This is spatial summation.

DEFINE the concept of quantal transmission.

Quantal transmission refers to the fact that signals are transmitted across chemical synapses in discrete packets, or quanta. Physically, each quantum is a neurotransmitter vesicle.

Quantal transmission is quantified by two terms, quantal content (Q_c) and quantal size (Q_s). Quantal content is the average number of vesicles released by a presynaptic cell, while quantal size is the average response to a single vesicle. Quantal size is derived from the average size of a miniature end-plate potential (miniEPP; miniEPPs result from the spontaneous release of a single vesicle), while quantal content is given by the average EPSP divided by the mean miniEPP amplitude.

DEFINE the function of excitatory and inhibitory ligand-gated ion channels.

Excitatory ligand-gated ion channels (or excitatory ionotropic receptors, such as AMPA and kainate receptors) are permeable to sodium (and usually other cations such as potassium), allowing the influx of depolarizing sodium current (an EPSC) upon binding their ligands, causing an EPSP.

Inhibitory ligand-gated ion channels (such as GABA-A and glycine receptors) are permeable to chloride, allowing an influx of hyperpolarizing chloride current (an IPSC) upon binding ligand, causing an IPSP.

DESCRIBE the reversal potential of postsynaptic currents.

The reversal potential of a PSC is the potential at which the IPSP or EPSP change directions. It depends upon the permeabilities of postsynaptic receptors to ions, and is given by the Goldman-Hodgkin-Katz voltage equation (the constant-field equation; see page 153 of Boron).

For a single-ion system (i.e. one in which the postsynaptic receptor is permeable to a single ion alone), the reversal potential is equal to the equilibrium potential for that ion. For example, in a receptor permeable only to chloride, the reversal potential is E_Cl, which is approximately -60 mV. In multi-ion systems in which postsynaptic receptors a permeable to several ions, the reversal potential depends upon the concentration and channel permeabilities of the receptor to the each of these ions. For example, the glutamate receptor, which is permeable to both sodium and potassium, has a reversal potential of 0 mV, given by the GHK equation. When receptors are equally permeable to potassium and sodium, the reversal potential is zero.

CONTRAST the structure of glutamate and GABA receptors.

All glutamate receptors (AMPA, kainate, and NMDA receptors) are ionotropic, while there are ionotropic and metabotropic variants of the GABA receptor.

Glutamate receptors are tetrameric, while ionotropic GABA receptors are pentameric. Both glutamate and ionotropic GABA receptors have four transmembrane domains. Glutamate receptors have a domain 2 that is sensitive to cations, while the domain 2 of ionotropic GABA receptors is sensitive to anions.

DESCRIBE the functional roles of NMDA vs. AMPA/kainate receptors.

NMDA and AMPA/kainate receptors are both glutamate-gated, but NMDA receptors have four differences -- they:

1. require glycine as a coactivator
2. are voltage-dependent due to Mg²⁺ blockade at rest (generates a negative I-V slope)
3. are more permeable to Ca²⁺ than to Na⁺ (though since there is more Na⁺, sodium will be the major permeant ion)
4. stay open 10 times longer than AMPA/kainate receptors

COMPARE fast and slow postsynaptic potentials.

Fast postsynaptic potentials are mediated by ionotropic receptors that respond quickly to ligand binding by opening ion channels intrinsic to the receptor. In contrast, slow PSPs are mediated by metabotropic (G protein-coupled) receptors that require a second messenger cascade in order to transduce the signal initiated by ligand binding.

For example, 5-HT works through a G_s protein-coupled receptor that activates a G_s protein, which activates adenylyl cyclase (AC). AC converts ATP to cAMP, which activates PKA, allowing PKA to phosphorylate and thereby inactivate potassium channels, resulting in a slow EPSP.

Similarly, the mAChR is a metabotropic receptor that generates slow IPSPs through the direct activation of potassium channels by associated G proteins (specifically the G_βγ subunits).