Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model

• Neuronal activity disrupts mGluR5-Homer interactions at synapses within minutes
• Disruption of mGluR5-Homer by activity requires CaMKIIα phosphorylation of Homer
• In fragile X syndrome model mice, Homer proteins are hyperphosphorylated by CaMKIIα
• Reduction of CaMKIIα levels or activity rescues fragile X phenotypes in mice

SummaryAbnormal metabotropic glutamate receptor 5 (mGluR5) function, as a result of disrupted scaffolding with its binding partner Homer, contributes to the pathophysiology of fragile X syndrome, a common inherited form of intellectual disability and autism caused by mutations in Fmr1. How loss of Fmr1 disrupts mGluR5-Homer scaffolds is unknown, and little is known about the dynamic regulation of mGluR5-Homer scaffolds in wild-type neurons. Here, we demonstrate that brief (minutes-long) elevations in neural activity cause CaMKIIα-mediated phosphorylation of long Homer proteins and dissociation from mGluR5 at synapses. In Fmr1 knockout (KO) cortex, Homers are hyperphosphorylated as a result of elevated CaMKIIα protein. Genetic or pharmacological inhibition of CaMKIIα or replacement of Homers with dephosphomimetics restores mGluR5-Homer scaffolds and multiple Fmr1 KO phenotypes, including circuit hyperexcitability and/or seizures. This work links translational control of an FMRP target mRNA, CaMKIIα, to the molecular-, cellular-, and circuit-level brain dysfunction in a complex neurodevelopmental disorder.

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