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BIO254:Silent: Difference between revisions
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Several experiments demonstrate that excitatory synapses can effectively regulate their postsynaptic glutamate receptors. For instance, when some glutamatergic synapses are stimulated, no postsynaptic electrical signal is generated when the postsynaptic cell is at a normal resting membrane potential. In contrast, when these same postsynaptic cells are depolarized, these "silent synapses" are able to transmit strong postsynaptic responses that are detectable using electrophysiological methods (such as patch clamp). Because these silent synapses have the potential to be turned on or off in response to postsynaptic activity, this mechanism demonstrates a simple means for modifying and regulating neural activity. | Several experiments demonstrate that excitatory synapses can effectively regulate their postsynaptic glutamate receptors. For instance, when some glutamatergic synapses are stimulated, no postsynaptic electrical signal is generated when the postsynaptic cell is at a normal resting membrane potential. In contrast, when these same postsynaptic cells are depolarized, these "silent synapses" are able to transmit strong postsynaptic responses that are detectable using electrophysiological methods (such as patch clamp). Because these silent synapses have the potential to be turned on or off in response to postsynaptic activity, this mechanism demonstrates a simple means for modifying and regulating neural activity. | ||
Silent synapses are abundant in development and are found in several brain regions, including the hippocampus, the cerebral cortex, and the spinal cord. The "silence" of these synapses is the result of Mg++ blockade of NMDA receptors, which are voltage-dependent. Interestingly, glutamate released at silent synapses binds only to NMDA receptors, without binding to AMPA receptors. For years, this specificity has puzzles neurobiologists, but one explanation is that NMDA and AMPA receptors have significantly different affinities for binding the released glutamate neurotransmitter. The concentration of glutamate may be sufficient enough to activate NMDA receptors (high-affinity), but not the low-affinity AMPA receptors. A second possibility states that both AMPA and NMDA receptors exist on the postsynaptic terminal, but only the NMDA receptors are fully functional. Or, some specific excitatory synapses only have NMDA receptors; growing evidence tends to support this latter model. Immunocytochemical experiments perhaps provide the most compelling evidence for this explanation: staining done by Gomperts et al. (2000) shows that select excitatory synapses only possess NMDA receptors. | Silent synapses are abundant in development and are found in several brain regions, including the hippocampus, the cerebral cortex, and the spinal cord. The "silence" of these synapses is the result of Mg++ blockade of NMDA receptors, which are voltage-dependent. Interestingly, glutamate released at silent synapses binds only to NMDA receptors, without binding to AMPA receptors. For years, this specificity has puzzles neurobiologists, but one explanation is that NMDA and AMPA receptors have significantly different affinities for binding the released glutamate neurotransmitter. The concentration of glutamate may be sufficient enough to activate NMDA receptors (high-affinity), but not the low-affinity AMPA receptors. A second possibility states that both AMPA and NMDA receptors exist on the postsynaptic terminal, but only the NMDA receptors are fully functional. Or, some specific excitatory synapses only have NMDA receptors; growing evidence tends to support this latter model. Immunocytochemical experiments perhaps provide the most compelling evidence for this explanation: staining done by Gomperts et al. (2000) shows that select excitatory synapses only possess NMDA receptors. These results support the first ("a") of two models for maturation of AMPA receptor signalling recently reviewed by Groc et al. (2006) and shown in Figure 1 below: | ||
[[Image:unsilencing.jpg]] | [[Image:unsilencing.jpg]] | ||
Figure 1. | Figure 1. Maturing of AMPA receptor signalling according to two models. (a) Glutamate synapses start without AMPA receptors, but acquire them subsequently, through exposure to correlated activity at pre- and post-synapses, thereby becoming mature AMPA-signalling receptors. (b) A second model involves glutamate synapses starting with AMPA receptors and switching readily between AMPA-signalling and AMPA-silent states as a function of the synaptic activation history. Correlated activity at pre- and post-synapses converts the early synapse from this switching behavior to mature, stable AMPA-signalling. | ||
(Groc et al., 2006) | (Groc et al., 2006) | ||
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Most excitatory synapses in the central nervous system are glutamatergic. In these synapses, glutamate released by the presynaptic cell acts on both metabotropic (mGluR) and ionotropic (iGluR) glutamate receptors in the postsynaptic membrane. Receptors in the iGluR channel can be classified as either NMDA (N-methyl-D-aspartate) or non-NMDA (kainate and AMPA) receptors. | Most excitatory synapses in the central nervous system are glutamatergic. In these synapses, glutamate released by the presynaptic cell acts on both metabotropic (mGluR) and ionotropic (iGluR) glutamate receptors in the postsynaptic membrane. Receptors in the iGluR channel can be classified as either NMDA (N-methyl-D-aspartate) or non-NMDA (kainate and AMPA) receptors. | ||
Non-NMDA receptors contribute to the early phase of the excitatory postsynaptic current (EPSC) and generate peak current, whereas NMDA receptors contribute to the late phase as a slower component, as can be seen in | Non-NMDA receptors contribute to the early phase of the excitatory postsynaptic current (EPSC) and generate peak current, whereas NMDA receptors contribute to the late phase as a slower component, as can be seen in Figure 2 below. This image also shows the effect of R-2-amino-5-phosphonopentanoate (APV), an inhibitor of NMDA receptors (see next section), on the EPSC: | ||
<div style="margin-left: 60px;">[[Image:iGluR_phases.png]]</div> | <div style="margin-left: 60px;">[[Image:iGluR_phases.png]]</div> | ||
