Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model
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 dis...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-12-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715013133 |
| _version_ | 1811289600670302208 |
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| author | Weirui Guo Laura Ceolin Katie A. Collins Julie Perroy Kimberly M. Huber |
| author_facet | Weirui Guo Laura Ceolin Katie A. Collins Julie Perroy Kimberly M. Huber |
| author_sort | Weirui Guo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T03:58:29Z |
| format | Article |
| id | doaj.art-26574830c75a4001b41783eb43d6c7c2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T03:58:29Z |
| publishDate | 2015-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-26574830c75a4001b41783eb43d6c7c22022-12-22T03:03:33ZengElsevierCell Reports2211-12472015-12-0113102297231110.1016/j.celrep.2015.11.013Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse ModelWeirui Guo0Laura Ceolin1Katie A. Collins2Julie Perroy3Kimberly M. Huber4Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACNRS, UMR-5203, Institut de Génomique Fonctionnelle, 34000 Montpellier, FranceDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USACNRS, UMR-5203, Institut de Génomique Fonctionnelle, 34000 Montpellier, FranceDepartment of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USAAbnormal 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.http://www.sciencedirect.com/science/article/pii/S2211124715013133 |
| spellingShingle | Weirui Guo Laura Ceolin Katie A. Collins Julie Perroy Kimberly M. Huber Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model Cell Reports |
| title | Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model |
| title_full | Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model |
| title_fullStr | Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model |
| title_full_unstemmed | Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model |
| title_short | Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model |
| title_sort | elevated camkiiα and hyperphosphorylation of homer mediate circuit dysfunction in a fragile x syndrome mouse model |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715013133 |
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