title: Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model.
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.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Weirui
authors.initials: W
authors.lastname: Guo
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, 34000 Montpellier, France; INSERM, U1191, 34000 Montpellier, France; Universites de Montpellier 1 & 2, UMR-5203, 34000 Montpellier, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Ceolin
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Katie A
authors.initials: KA
authors.lastname: Collins
authors.affiliation: CNRS, UMR-5203, Institut de Génomique Fonctionnelle, 34000 Montpellier, France; INSERM, U1191, 34000 Montpellier, France; Universites de Montpellier 1 & 2, UMR-5203, 34000 Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Perroy
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: kimberly.huber@utsouthwestern.edu.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004594:Electrophysiology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002352:Carrier Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D000072233:Homer Scaffolding Proteins; D064529:Receptor, Metabotropic Glutamate 5; C497684:Fmr1 protein, mouse