Synaptic ER · Understanding mechanisms regulating endoplasmic reticulum dynamics in hippocampal synaptic plasticity

Dendritic spines are microdomains with dynamic distribution of ionotropic glutamate receptors and associated proteins involved in synaptic transmission. In the hippocampus, two forms of long-lasting changes in synaptic activity — long-term potentiation and long-term depression (LTD) — are thought to underlie learning and memory processes. Of the three ionotropic glutamate receptors, it is the AMPA receptor (AMPAR) that mediates the majority of fast excitatory synaptic transmissions in spines. Most AMPARs are calcium impermeable. The incorporation of AMPAR GluA2 subunit is important for this functional characteristic and this occurs before the exit from endoplasmic reticulum (ER). ER is dynamically distributed in subpopulations of hippocampal dendritic spines. These ER-containing spines can play important roles in many neuronal functions, and ER expulsion from spines is likely to affect spine signaling and plasticity. But whilst research on receptor trafficking and the associated postsynaptic protein complex has greatly advanced our understanding on LTD, the contribution of spine ER dynamics has been over-looked. In this connection, the present proposal aims to test the hypothesis that dynamic ER distribution in spines can contribute to synaptic plasticity by elucidating whether there are any common mechanisms regulating AMPAR GluA2 subunits and ER dynamics in relation to metabotropic glutamate receptor dependent LTD induction. This is a novel approach and requires combination of advanced live-cell imaging and electrophysiological recordings to study how the structural and functional plasticity in a single spine accords with the dynamic change in ER and the intracellular molecular events. It is anticipated that this research will shed insights into the physiologies and pathophysiologies of synaptic ER and contribute to a significant step forward in synaptic research.