Role of Altered mGluR Activity in Cognitive Impairments in TSC: Implications for a Novel Method of Treatment
Abstract
The goal of this project is to determine the underlying synaptic dysfunction in Tuberous Sclerosis Complex (TSC). Scope: TSC is a multi-system genetic disorder with central nervous system dysfunction as a defining factor. The most common clinical features are mental retardation, epilepsy, autism, anxiety and mood disorders. Fragile X syndrome (FXS), another form of inherited mental retardation and autism, shares many of the same molecular and clinical features. Much of the pathophysiology in FXS can be ameliorated through modulation of Group 1 metabotropic glutamate receptors (mGluRs). Since both disorders share key features suggests that they may also share common pathogenic mechanisms. Therefore, determined whether altered synaptic protein synthesis, plasticity and hippocampal-dependent behavior could be ameliorated through modulation of mGluR s in a mouse model of TSC. Major findings: Unlike in FXS where negative modulation of mGluR s has proven beneficial, we found that augmenting mGluR function either genetically or through application of an mGluR5 positive allosteric modulator (PAM) ameliorates several of the synaptic and hippocampal-dependent behavioral deficits observed in a mouse model of TSC. Significance: These results suggest that modulation of mGluR activity with PAMs may be a therapeutic intervention for several of the deficits observed in TSC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2013
- Accession Number
- ADA580192
Entities
People
- Mark Bear
Organizations
- Massachusetts Institute of Technology