A tale of two tails: Regulation of AMPA receptor function through C-terminal interactions.

摘要

Synapses exist in different states and their potential to undergo activity-dependent changes is determined by both their present state and their recent history. Two commonly studied forms of synaptic plasticity are long-term potentiation (LTP) and long-term depression (LTD), and these have been found to correlate with increases or decreases in the number of AMPA receptors in the postsynaptic membrane, respectively. AMPA receptors bind to a variety of intracellular proteins via their C-terminal tails, and these interactions are thought to be important for regulating AMPA receptor trafficking and, therefore, synaptic plasticity.; To test this hypothesis, interactions between the GluR1 C-terminus and its binding proteins were disrupted and the effects on synaptic transmission were determined. This was accomplished by perfusing a peptide corresponding to the GluR1 C-terminus into the postsynaptic neuron while recording from synaptically connected pairs of CA3 pyramidal neurons in organotypic hippocampal slices. AMPA-mediated EPSCs decreased in amplitude by about 50% in the basal state, while potentiated EPSCs did not exhibit such a run down following the induction of LTP. The selective loss of GluR1-containing AMPA receptors following infusion of peptide was confirmed using immunocytochemistry. Consistent with the theory that only GluR2/3 receptors are internalized during LTD, the peptide did not disrupt its induction. Therefore, GluR1 C-terminal interactions seem to be necessary for the stabilization of AMPA receptors at the synapse only when in the basal state. In contrast, these C-terminal interactions do not seem to be necessary for GluR1 stabilization in the potentiated state.; In a second set of experiments, GRIP1-GFP was overexpressed in postsynaptic neurons of connected CA3-CA3 pairs in order to examine whether the interaction between GluR2 C-terminus and GRIP1 was important for synaptic transmission. GRIP1-GFP overexpressing neurons could not be potentiated, suggesting that GRIP1 might be involved in synaptic plasticity. Furthermore, LTD was inducible in GRIP1-GFP overexpressing neurons, indicating that the mechanisms for retrieval of AMPA receptors from the synapse were not affected. Taken together, these data further our understanding of the molecular mechanisms that govern AMPA receptor trafficking within the synapse, and suggest that these mechanisms can differ depending on the synaptic state.