Molecular Adaptations to Cholinergic Interneuron Ablation in a Novel Mouse Model of Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
Yale University
Investigators Name
Xu, Meiyu, PhD

Tourette syndrome (TS) is a prevalent neuropsychiatric disorder for which available treatments are frequently inadequate and new neurobiological insights are urgently needed. Recent post-mortem studies have revealed a 50%–60% decrease in tonically active cholinergic neurons (TANs) in the associative and sensorimotor regions of the striatum in TS, thereby establishing a potential link between these interneurons and TS symptomatology. However, the role of TANs in the development of TS pathology remains unclear. We are developing a mouse model, using a combination of transgenic and viral methodologies, in which the TANs are selectively ablated in the dorsal striatum. Our approach uses a cre-activated recombinant adeno-associated virus expressing a toxin receptor (diphtheria toxin receptor, or DTR), infused into mice expressing cre recombinase specifically in TANs. Unbiased microarray analysis will be used to reveal genes that are differentially regulated as the result of TAN ablation in the striatum by comparing DT treated and non-DT treated mice. Candidate genes will be confirmed using real-time Polymerase Chain Reaction (PCR). This molecular analysis will identify perturbed receptors, signaling pathways, and other molecular events that may represent novel drug targets. One specific hypothesis is that TAN ablation will lead to an imbalance between direct and indirect pathways in the basal ganglia, which is believed to contribute to neuropathology in TS. In addition, we will examine D1 and D2 dopamine receptorsusing in vitro radioligand binding. If, as predicted, alterations in dopamine and its receptors are found in these experiments, downstream signaling will be examined as well. Characterization of specific alterations in these pathways in this mouse model will generate specific hypotheses for testing in other models and in clinical studies. Meiyu Xu, Ph.D., Christopher Pittenger, MD, Ph.D. Yale University, New Haven, CT Award: $40,000 (Fellowship) Commentary: Tourette syndrome (TS) is a neurological disorder in which a person has both motor and vocal tics. Although we don’t know the exact cause of TS, it occurs when there is a problem with how nerve cells communicate in the brain. Recent post-mortem studies of brain tissue taken from people who had TS have revealed a significant decrease in a specific type of nerve cell (TANs) in a part of the brain called the striatum. This finding suggests a potential link between these nerve cells and TS symptomatology. The authors plan to develop a mouse model in which the TAN cells in the striatum have been removed, and to determine the effect that this has on brain function. Tourette Association of America Inc. – Research Grant Award 2011-2012