Regulation Of Synaptic Scaling By The C-terminal Domain(CTD) Of AMPAR Subunits GluA1 And GluA2

Homeostatic synaptic plasticity is a cellular mechanism that can counteract changes brought by LTP and LTD to stabilize neuronal network activity within certain range.Synaptic scaling,the most extensively studied form of homeostatic synaptic plasticity,is mainly expressed by alterations in postsynaptic AMPA receptors(AMPAR).However,the specific role of GluA1 and GluA2,the predominant subunits of AMPARs,in synaptic scaling is unclear.In addition,although the CTD of AMPARs is critically important for AMPAR trafficking and expression of LTP and LTD,its role in synaptic scaling remains unknown.To date,the main approaches to assess the involvement of AMPARs in synaptic scaling have been through the peptide inhibition or molecular transfection to achieve perturbations at the CTD,but they suffer non-specific effects and are not able to address the role of endogenous GluA1 and GluA2.In this thesis project,We employed knock-in mouse models where the CTD of the endogenous GluA1 and GluA2 is specifically altered.Two mutant mice were used:GluA1C2 KIwhere the CTD of GluA1 was replaced by that of GluA2 and GluA2C1 KI where the CTD of GluA2 was replaced by that of GluA1.Through a series of experimental methods,including electrophysiology,biochemistry,and animal behavior,We show that the CTD of GluA2,but not GluA1,is required for synaptic scaling up in response to TTX treatment through synaptic accumulation of AMPARs.In contrast,the CTD of GluA1,but GluA2,is required for synaptic scaling down in response to bicuculline treatment.These results provide strong evidence that the CTDs of endogenous GluA1 and GluA2 play distinct roles in synaptic scaling.