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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Autistic Disorder, Carrier Proteins, Disease Models, Animal, Male, Mice, Mice, Inbred C57BL, Mutation, Nerve Tissue Proteins, Neuronal Plasticity, Neurons, Phosphorylation, Prefrontal Cortex, Receptors, AMPA, Social Behavior, Synapses
Mol Psychiatry
Date: May. 01, 2026
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