Dysregulated GluA2-Y876 phosphorylation contributes to loss of synaptic upscaling in GRIP1 mutant mice with reduced sociability and increased repetitive behavior.

Abstract

Loss of synaptic upscaling, a post-synaptic homeostatic plasticity, has been reported in mouse models of autism, but the underlying mechanism remains unknown. Glutamate receptor interacting protein 1 (GRIP1) binds AMPA receptor 2 (GluA2) through its PDZ domains 4-6 where gain-of-function variants were described in autism. We characterized mice carrying one variant, GRIP1-I586L (murine I507L), that shows increased binding with GluA2. Grip1-I507L mice exhibit impaired social interaction and increased repetitive behaviors, increased neuronal excitability and excitatory-to-inhibitory ratio in the medial prefrontal cortex. Grip1-I507L cortical neurons show a loss of synaptic upscaling to tetrodotoxin-induced inactivity. Basal phosphorylation of GluA2-Y876 is increased, which is consistent with increased binding to GluA2 while lack of further induction to inactivity contributes to loss of synaptic upscaling. Phosphorylation of GluA2-S880 that regulates Hebbian plasticity is not altered. These results support that gain-of-function GRIP1 variants are a novel cause of autism-related impaired social interaction and increased repetitive behavior and implicate that dysregulated phosphorylation of GluA2-Y876 is a novel mechanism for loss of synaptic upscaling.