AMPA receptor trafficking and synaptic plasticity

grantor: University of TorontoAMPA receptors are a subtype of glutamate receptors which are responsible for most of the fast excitatory synaptic transmissions in the mammalian central nervous system. The redistribution of postsynaptic AMPA receptors has been proposed as a mechanism for synaptic plasticities, including long-term potentiation (LTP) and long-term depression (LTD), two cellular models for learning and memory. However, direct evidence to support this hypothesis is still lacking and the cellular mechanisms mediating AMPA receptor trafficking are poorly understood. We therefore set up to investigate the involvement of AMPA receptor trafficking in both LTD and LTP. We found that AMPA receptors undergo endocytosis via a clathrin-coated-pit pathway, and that the internalization can be accelerated by insulin in a GluR2 subunit-dependent manner. The insulin-stimulated endocytosis rapidly decreased the number of AMPA receptors in the plasma membrane, resulting in an LTD of AMPA receptor-mediated synaptic transmission in hippocampal CA1 neurons. Moreover, insulin-induced LTD and low-frequency-stimulation (LFS)-induced hippocampal CA1 homosynaptic LTD were found to mutually occlude each other and both were blocked by inhibiting postsynaptic clathrin-mediated endocytosis. These data indicate that controlling the number of postsynaptic receptors by endocytosis may be an important mechanism underlying LTD in the mammalian CNS. On the other hand, although AMPA receptor insertion is an attractive cellular model for LTP expression and is gaining increasing support in recent years, the underlying mechanisms for AMPA receptor translocation are still unknown. We found here that the phosphoinositide kinase PI3-kinase (PI3K) directly associates and co-localizes with AMPA receptors. Selective activation of synaptic NMDA receptors by the NMDA receptor co-agonist glycine activates the AMPA receptor-associated PI3K and induces long-term potentiation (LTP) of AMPA mini-EPSCs. Furthermore, brief glycine treatment induces increases in cell-surface expression of AMPA receptors and the increase is due to an enhancement in receptor plasma membrane insertion. Consistently, the glycine-induced LTP is blocked by inhibiting receptor insertion. Moreover, PI3K activation is also shown to be necessary in the expression of homosynaptic LTP in hippocampal CA1 neurons. These data provide evidence for an NMDA receptor-PI3K-AMPA receptor translocation mechanism in LTP generation.Ph.D