Analysis of the Role of the Functional Loss of Neuron Populations Associated with Tourette Syndrome in the Symptomatology of the Disorder

Grant Type
Basic
Grant Year
2011-2012
Institution Location
NJ
Institution Organization Name
Rutgers University
Investigators Name
Koos, Tibor, PhD

An important task towards understanding the neuronal mechanism of Tourette syndrome is to determine which cellular abnormalities associated with the disorder are necessary and sufficient to generate abnormal motor behavior in experimental animals that replicate the key characteristics of the disorder. Significant loss of 3 neuronal populations (fast-spiking GABAergic and cholinergic interneurons of the caudate- putamen and GABAergic projection neurons of the external globus pallidus) have been demonstrated in Tourette syndrome. We will examine the possible causal role of the loss of these neuron populations in the symptomatology of the disorder using temporally precise brief optogenetic inhibition or chronic ablation of one or more of these cell populations in mice. Cell type specific expression of optogenetic tools or a neurotoxin will be achieved with viral mediated gene transfer in transgenic mice and quantitative behavioral analysis will be performed. The application of the acute (optogenetic) inhibition or chronic ablation approaches will allow us to ascertain whether the abnormal symptoms arise as result of a direct and immediate alteration of the dynamics of the local circuitry or are secondary to more slowly developing adaptive changes. We will pay particular attention to a precise characterization of the structure and temporal pattern of the elicited hyperkinetic (or other) motor effects of these interventions to evaluate the degree to which characteristics of the human disorder can be replicated. These experiments are expected to provide useful insight into the neuronal circuit mechanism of the symptomatology of Tourette syndrome. Tibor Koos, Ph.D. Rutgers University, Newark, NJ Award: $65,540 Commentary: Tourette syndrome (TS) is an often debilitating neurological disorder that affects a large number of children and many adults. Although certain drugs and invasive surgical procedures can improve the symptoms of patients, these treatments are often unsatisfactory. Development of better therapies requires an animal model of the disorder so that the causes of the disorder and new treatments can be investigated in the laboratory. The authors will use modern molecular biological methods to reproduce in mice, some of the abnormalities that are commonly observed in the brain of people with TS and examine which of these abnormalities (if any) cause symptoms that match the symptoms of people with TS. Tourette Association of America Inc. – Research Grant Award 2011-2012