The Role of Intracellular Signaling Pathways in Endophenotypes of Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Pennsylvania
Investigators Name
Kelly, Michele, PhD

Those with Tourette’s syndrome (TS) exhibit involuntary motor and vocal tics and show impaired sensorimotor gating. Sensorimotor gating is an attentional process whereby an individual filters out extraneous incoming sensory information in order to focus attention on specific relevant stimuli. These symptoms negatively impact a person’s quality of life by compromising self-esteem and familial/peer relationships. Alterations in several chemicals that communicate between nerve cells in the brain (called neurotransmitters) have been implicated in the etiology of TS. The cAMP second messenger cascade is one intracellular signaling pathway that is regulated by each of the neurotransmitters that have been implicated in the etiology of TS. Interestingly, decreased levels of the cAMP molecule have been observed in the cortex of people with TS. The goal of this project is to identify how these decreases in cAMP signaling within specific brain regions might contribute to symptoms of TS. Our laboratory utilizes genetically modified mice to investigate which intracellular signaling molecules contribute to the attentional processing of sensorimotor gating. Mice can be genetically modified in a number of ways in order to study the potential contribution of a particular molecule or signaling pathway to a given behavior. For example, DNA that encodes a particular gene of interest can be removed so that the mouse no longer expresses the molecule that the gene encodes. Alternatively, DNA can be added so that the mouse expresses higher levels of a given molecule than normal. The behavior of a genetically modified mouse is then compared to a sibling whose DNA has not been altered. If the genetically modified mouse demonstrates a change in behavioral performance relative to its sibling, then we can conclude that the gene of interest plays a role in that behavior. Also, the expression and activity levels of other molecules can be measured to determine whether the genetic alteration is what triggered any compensatory changes. Finally, we can determine whether specific drugs have a different effect on the behavior of genetically modified versus unmodified mice. By combining these approaches, we will determine how cAMP mediates symptoms of the disorder and, thus we may identify novel therapeutic approaches that better treat symptoms of TS. Michele P. Kelly, Ph.D. University of Pennsylvania, Philadelphia, Pennsylvania Award: $40,000 Tourette Association of America Inc. – Research Grant Award 2005-2006