Cholinergic Interneurons in Tourette Syndrome

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Tourette syndrome (TS) is a common childhood-onset neurodevelopmental disorder characterized by multiple motor and phonic tics. TS is accompanied commonly by behavioral co-morbidities, including obsessive compulsive disorder (OCD) and attentional deficits. The pathogenesis and pathophysiology of TS are understood only poorly. Converging evidence points to striatal dysfunction in TS and a modest amount of post-mortem data suggests deficits in some populations of striatal interneurons, notably cholinergic interneurons. Striatal cholinergic interneurons are important actors within the basal ganglia. This relatively sparse population of interneurons may serve a synchronizing role across large volumes of the striatum. Deficient striatal cholinergic interneurons are a plausible substrate for tics and related manifestations of TS and we hypothesize diminished striatal cholinergic interneurons in TS. It has not been previously feasible to quantify striatal cholinergi interneuron integrity in vivo. Our group developed a novel positron emission tomography (PET) tracer, [18F]FEOBV, a ligand for the vesicular acetylcholine transporter (VChT), that allows accurate quantification of striatal cholinergic terminals in humans. We propose to evaluate striatal cholinergic neuron terminal integrity in TS and control subjects. We will recruit TS and age-matched control subjects for study with [18F]FEOBV. Subjects will undergo a standard clinical evaluation including assessment of tic severity and character, obsessive-compulsive behaviors, and attentional deficits. Primary analysis will be comparison of striatal [18F]FEOBV binding between TS and control subjects. Secondary analyses will include correlation of striatal [18F]FEOBV binding with clinical ratings and assessment of cholinergic terminal integrity in other brain regions. Validation of this hypothesis would point to a specific anatomic - neurochemical system deficit in TS. This would facilitate research on understanding the developmental basis for TS. Cholinergic systems offer multiple potential targets for pharmacologic intervention and validation of this hypothesis would initiate a new approach to experimental therapeutics in TS.