AMPA receptor regulation during synaptic plasticity in hippocampus and neocortex

Abstract

Discovery of long-term potentiation (LTP) in the dentate gyrus of the rabbit hippocampus by Bliss and Lømo opened up a whole new field to study activity-dependent long-term synaptic modifications in the brain. Since then hippocampal synapses have been a key model system to study the mechanisms of different forms of synaptic plasticity. At least for the postsynaptic forms of LTP and long-term depression (LTD), regulation of AMPA receptors (AMPARs) has emerged as a key mechanism. While many of the synaptic plasticity mechanisms uncovered in at the hippocampal synapses apply to synapses across diverse brain regions, there are differences in the mechanisms that often reveal the specific functional requirements of the brain area under study. Here we will review AMPAR regulation underlying synaptic plasticity in hippocampus and neocortex. The main focus of this review will be placed on postsynaptic forms of synaptic plasticity that impinge on the regulation of AMPARs using hippocampal CA1 and primary sensory cortices as examples. And through the comparison, we will highlight the key similarities and functional differences between the two synapses.

Figure 1. A model of AMPAR regulation

AMPARs reside in distinct subcellular compartments as depicted. Exocytosis from recycling endosome to extrasynaptic sites depends on GluA1-S845 phosphorylation. PKA-linked neuromodulators increase the extrasynaptic GluA1 population via acting on GluA1-S845. Interestingly, cortical synapses have a smaller basal extrasynaptic GluA1 population compared to CA1. Extrasynaptic population can laterally diffuse into synaptic areas, and synaptic activity traps and anchors them to the PSD. Synaptic targeting depends on GluA1-S818 phosphorylation and CaMKII activity, as well as prior phosphorylation on the GluA1-S845, but not on the GluA1-S831. Synaptic AMPARs can be endocytosed via perisynaptic endocytic zones, which also act to supply AMPAR to recycling endosomes. Dephosphorylation of GluA1-S845 targets endocytosed AMPARs to lysosome for degradation, while phosphorylation of this site allows recycling back to the plasma membrane. CP-AMPARs predominantly accumulate at perisynaptic sites in CA1, while accumulate at cortical synapses with changes in sensory experience.