Ca-permeable AMPA receptors in homeostatic synaptic plasticity

Abstract

Neurons possess diverse mechanisms of homeostatic adaptation to overall changes in neural and synaptic activity, which are critical for proper brain functions. Homeostatic regulation of excitatory synapses has been studied in the context of synaptic scaling, which allows neurons to adjust their excitatory synaptic gain to maintain their activity within a dynamic range. Recent evidence suggests that one of the main mechanisms underlying synaptic scaling is by altering the function of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), including synaptic expression of Ca(2+)-permeable (CP-) AMPARs. CP-AMPARs endow synapses with unique properties, which may benefit adaptation of neurons to periods of inactivity as would occur when a major input is lost. This review will summarize how synaptic expression of CP-AMPARs is regulated during homeostatic synaptic plasticity in the context of synaptic scaling, and will address the potential functional consequences of altering synaptic CP-AMPAR content.

Keywords: CP-AMPAR; GluA1; activity-dependent; homeostasis; inactivity; synaptic scaling.

Figure 1

Regulation of CP-AMPARs in homeostatic synaptic plasticity. (A) Inactivity-induced synaptic expression of CP-AMPARs. Inactivity leads to local synthesis of GluA1. One mechanism is via RA signaling, where RA binds to RARα to relieve translational inhibition of GluA1 mRNA. Newly synthesized GluA1 containing CP-AMPARs are then eventually trafficked to the synapse (PSD, postsynaptic density). Cell surface expression of GluA1 containing CP-AMPARs is likely tied to phosphorylation of GluA1-S845. In visual cortex, the increase in extrasynaptic GluA1 leads to synaptic accumulation, however, in hippocampus an extra regulatory step from perisynaptic to synaptic trafficking may be needed. Inactivity driven synaptic localization of CP-AMPARs also depend on CaMKIIβ activity, which may act on GluA1-S831 phosphorylation. Synaptic expression of CP-AMPARs may occur in conjunction with removal of CI-AMPARs via GluA2-dependent mechanisms. (B) Removal of synaptic CP-AMPARs following an increase in neural activity. The increase in neuronal activity following a period of inactivity results in up-regulation of immediate early genes such as Arc and Homer1a. Both of these proteins lead to endocytosis of AMPARs. However, this process is not likely specific to CP-AMPARs and would result in removal of CI-AMPARs as well (not depicted in the figure). Homer1a acts to produce agonist-independent activation of Group 1 mGluRs by displacing long forms of Homer1. Homer1a signaling is specific for activity-dependent homeostatic scaling down of excitatory synapses. On the other hand, Arc is also involved in AMPAR endocytosis following mGluR-LTD.