The role of Intracellular Signaling Pathways in Endophenotypes of Tourette’s Syndrome (2nd year)

Grant Type
Basic
Grant Year
2006-2007
Institution Location
PA
Institution Organization Name
University of Pennsylvania
Investigators Name
Kelly, Michele, PhD

Patients with Tourette Syndrome (TS) have impaired sensorimotor gating. This prevents them from filtering out extraneous incoming sensory information in order to focus attention on specific and relevant stimuli. While several chemicals (neurotransmitters) that communicate between nerve cells have been implicated in the etiology of TS, little is known about which molecules are important for signaling within nerve cells. The cAMP second messenger cascade is an intracellular (within cells) signaling pathway that is regulated by each of the neurotransmitters that have been implicated in TS. Interestingly, decreased levels of cAMP have been observed in the cells of the cortex of patients with TS (Singer et al.; 1990). The goal of this project is to identify how a decrease in intracellular cAMP within specific brain regions may contribute to cause the symptoms of TS. Mice can be genetically modified in a number of ways in order to study the contribution of a particular molecule or signaling pathway to a given behavior. The effect of specific drugs on the behavior of genetically modified versus unmodified mice can also be determined. Our laboratory utilizes genetically modified mice to investigate which intracellular signaling molecules contribute to the attentional processing of sensorimotor gating. During the first year of this award, we showed that in genetically modified mice, decreased cAMP signaling within the brain leads to sensorimotor gating deficits. This led us to hypothesize that drugs that work inside the cell to increase cAMP levels may prove useful for treating TS. We confirmed our hypothesis by showing that a drug known as Rolipram, which reduces degradation of cAMP, fully relieves the sensorimotor gating deficits exhibited by our genetically modified mice. Thus, we have identified a novel class of drugs that may have potential for treating TS. In the second year of this award we will focus on determining 1) which brain regions mediate the observed effects, 2) how juvenile development may play a role in the observed effects, and 3) whether drugs that stimulate other molecules in the cAMP cascade show similar properties. We are very hopeful that this research will contribute additional information about treatment for TS. Michele P. Kelly, Ph.D. University of Pennsylvia, Philadelphia, Pennsylvania Award: $40,000 (2nd Year) Tourette Association of America Inc. – Research Grant Award 2006-2007