John J. Marshall - US grants

DESCRIPTION (provided by applicant): Obsessive Compulsive Disorder (OCD) is a chronic anxiety disorder characterized by maladaptive compulsive behavior such as excessive grooming, hoarding or checking. OCD is a debilitating disease, estimated to affect 1-2% of the population, making it the fourth most common mental illness after depression, alcoholism and social anxiety disorder. Despite innovations in pharmacological, behavioral, and surgical treatments at least 30% of cases prove intractable. Recent advances in understanding the neurobiological underpinnings of OCD have highlighted a central role for dysfunction of the glutamate system, the brain's major excitatory neurotransmitter, in the subcortical region of the striatum. In addition to clinical literature linking OCD to alterations in striatal activity, anima studies have indicated that the synapses formed by cortical neurons onto striatal spiny projection neurons (SPNs) are crucial in regulating habit formation. This convergent evidence indicates that perturbations in normal striatal activity will be crucial to understanding the emergence of maladaptive compulsive, habitual behavior seen in patients with OCD. Mice lacking expression of the kainate receptor, a subtype of glutamate receptor, have a dramatic compulsive grooming and anxiety phenotype reminiscent of that seen in OCD. Despite being highly expressed in the striatum, it is not known how kainate receptors contribute to striatal synaptic transmission and plasticity, and therefore to the overall regulation of the striatal circut. Preliminary work has determined that, in the striatum, activating kainate receptors facilitates the release of endocannabinoids. This is a novel interaction that has not been previously demonstrated. Endocannabinoids are common neuromodulators that serve to down-regulate transmitter release at synapses throughout the brain. I hypothesize that this coupling of kainate receptors to endocannabinoids provides a physiologically relevant method of regulating glutamate release in the striatum that is highly important for the behavioral phenotype of kainate receptor knockout mice. The following aims propose to determine the biochemical mechanism by which kainate receptors couple to endocannabinoids and the contribution of this interaction to normal striatal synaptic function and plasticity. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive Disorder (OCD) is a debilitating disease characterized by maladaptive compulsive or habitual behavior that is estimated to affect 1-2% of the population. We have developed a novel mouse model of OCD to help elucidate how changes in synaptic transmission in specific brain regions give rise to habitual behavior. While currently 30% of OCD cases are intractable, understanding these biochemical and synaptic abnormalities will lead to treatments that are more effective, specific, and give rise to fewer complications.