Molecular Control of Inhibition in D1-MSNs in Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Maryland School of Medicine
Investigators Name
Lobo, Mary K, PhD

Dysfunction of basal ganglia output-pathways arising from D1 receptor (direct-pathway) vs. D2 receptor (indirect-pathway) containing striatal medium spiny neurons (MSNs) is implicated in the stereotyped movements that characterize Tourette Syndrome (TS). Despite this proposed dysfunctional role for MSN subtypes in TS and other developmental neurological disorders characterized by stereotypic movements, there is minimal information on the molecular and functional role of either MSN subtype in these disorders. In this proposal, we will use cell type specific gene expression profiling, chromatin immunoprecipitation (ChIP), and optogenetics to understand the selective role of D1-MSNs in TS related behaviors. We have a mouse model that displays involuntary stereotypic behaviors during juvenile and early adult ages. These mice have a deletion of TrkB, the receptor for BDNF, in D1-MSNs (D1-Cre-fITrkB mice). These mice display down-regulation of many GABA-A subunits in the striatum, which is accompanied by decreased inhibition in striatal D1-MSNs. This is consistent with recent studies implicating a role for a dysfunctional GABAergic system in TS patients. D1-Cre-fITrkB mice also display a down-regulation of the BDNF-TrkB signaling pathway target, the transcription factor early growth response 3 (Egr3), in striatum. Since Egr3 transcriptionally regulates a subset of GABA-A subunits, we predict that decreased Erg3 transcriptional regulation of GABA-A subunits in D1-MSNs causes blunted inhibition of these MSNs leading to stereotypic behaviors. The goals of this study are to: 1. Examine Egr3 and GABA-A subunits gene expression in striatal D1-MSNs in an animal model of stereotypy. 2. Examine Egr3 transcriptional regulation of GABA-A subunits in an animal model of stereotypy 3. Determine if overexpressing Egr3 in D1-MSNs or optogenetic inhibition of D1-MSNs can rescue the stereotypic behaviors in an animal model of stereotypy. Mary K. Lobo, Ph.D. University of Maryland School of Medicine, Baltimore, MD Award: $150,000 Tourette Association of America Inc. – Research Grant Award 2014-2015