Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome
Kimberly Huber, PhD
Principal Investigator
Weirui Guo, PhD
FRAXA Fellow
University of Texas at Southwestern
Houston, TX
2012-2013 Grant Funding: $90,000
With support from The Meadows Foundation of/for Texas
Summary
Dr. Kimberly Huber and Dr. Weirui Guo at the University of Texas at Soutnwestern investigated the roles of Homer and CaMKII in Fragile X syndrome.
The Results
This project helped uncover how Fragile X disrupts key signaling “scaffolds” that organize communication at synapses. The team showed that elevated CaMKIIα activity and excessive phosphorylation of the Homer scaffold contribute to circuit dysfunction in the Fragile X mouse model, strengthening the case that restoring normal mGluR5–Homer organization (or the upstream regulators that control it) could be a viable therapeutic strategy.
Published 2015: Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model
Follow-up published 2016: Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice
The Science
Developmental Study of FMRP Dependent Synapse Regulation in Fragile X Syndrome
Enhanced metabotropic glutamate receptor subunit 5 (mGluR5) function is causally associated with the pathophysiology of Fragile X syndrome. Little is known about the molecular mechanisms that cause overactive mGluR5 in Fragile X. mGluR5 is less associated with its intracellular scaffolding protein, Homer, in Fragile X syndrome mice (Fmr1 KO) which is linked with overactive mGluR5 and mGluR5 dysfunction in Fragile X. Drs. Guo and Huber tested their hypothesis that enhanced phosphorylation of Homer by a specific Homer kinase, CaMKII, occurs in the brains of Fmr1 KO mice and leads to enhanced mGluR5 function and Fragile X phenotypes. These experiments would determine if Homer kinases, such as CamKII, could be therapeutic targets for Fragile X syndrome.
Grant Post Revisions
- 2013/09 - Published.
- 2015/09 - Results added.