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

Weirui Guo, Laura Ceolin, Katie A. Collins, Julie Perroy, Kimberly M. Huber

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Abstract

Abnormal 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. Abnormal mGluR5 function contributes to the pathophysiology of fragile X syndrome. Guo et al. find that elevated protein levels and activity of CaMKIIα and hyperphosphorylation of the mGluR5 scaffolding Homer proteins mediate the mGluR5 dysfunction and circuitry pathophysiology in Fmr1-/y mice.

Original languageEnglish (US)
JournalCell Reports
DOIs
Publication statusAccepted/In press - May 14 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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