The involuntary, repetitive movements that characterize TS are likely generated by the defective functioning of specific neuronal circuits in the brain. Animal models are useful in investigating the pathology that underlies the generation of involuntary movements. In this study, we will investigate a genetically modified mouse line, which displays abnormal, repetitive, involuntary movements, exacerbated by stress – rather similar to “tics†in humans. The mutated gene encodes a voltage-gated ion channel, named HCN1 (hyperpolarization-activated cyclic nucleotide sensitive channel 1), which is normally expressed at very high levels in a limited set of neuronal populations: corticostriatal and cortico-spinal projection neurons (layer V pyramidal), parvalbumin positive interneurons, cerebellar Purkinje neurons, inferior olive and alphamotoneurons. We propose to identify which specific neuronal class is responsible for generating the abnormal movements observed in HCN1 knockout mice. We will do this by using genetic targeting techniques to ablate channel activity in one neuronal class at a time. To aid in the detection of areas important for the generation of involuntary movements, we will combine our genetic targeting approach with an imaging approach. We will image the brains of wild-type and mutant animals using positron emission tomography (PET) scanning, following injection of 2-[18F]-fluoro-2-deoxy-D-glucose (FDG), which allows the detection of regional abnormalities in brain metabolism as a marker of abnormal brain activity. By comparing results from the imaging and genetic targeting experiments we will further determine whether the primary neuronal defect manifests at the site of origin, or rather at other sites in the brain that are important for movement control, presumably due to the connections existing between distinct brain regions. Our findings may reveal new and important pathways for involuntary movement generation, along with potential strategies for intervention through the targeting of voltage-gated ion channels in the brain. Bina Santoro, Ph.D. Columbia University, New York, NY Award: $75,000 Commentary: Repetitive, involuntary movements, such as those that characterize Tourette syndrome, can be reproduced in specially bred animals. This investigator has identified a line of genetically modified mice, in which inactivation of a single gene results in an abnormal, repetitive movement sequence very similar to a “tic.†The affected gene, named HCN1, controls the generation of electrical signals in multiple regions of the brain. Using genetic manipulation and brain imaging techniques, the author will determine which particular brain area is responsible for producing such involuntary behavior in mice. This research will shed light on the mechanisms that control abnormal movements and may help identify new targets for therapeutic interventions. Tourette Association of America Inc. – Research Grant Award 2011-2012
A New Genetic Mouse Model to Investigate the Pathophysiology of Involuntary Movement Disorder
Grant Type
Basic
Grant Year
2011-2012
Institution Location
Institution Organization Name
NY
Investigators Name
Santoro, Bina, PhD