DESCRIPTION (provided by applicant): Dystonia is a severe motor disorder that causes painful muscle contractions. Genetic defects cause it, yet in many cases it can also arise spontaneously at any time in life. In every case, dystonia arises because the brain's motor circuits are compromised, and defects in the basal ganglia are by far the most heavily implicated source. But recently, the cerebellum has emerged as a major new origin. However, it's still not clear how the cerebellum contributes to dystonia. Therefore, when I started this project I wanted to test if obstructing cerebellar communication triggered dystonia, and if it did, I thought it woud be important to test how the defective signals destroy movement. I hypothesized that blocking certain cerebellar synapses would cause ataxia, whereas blocking others might cause dystonia. To address my question, I first devised an experimental model that would enable me to systematically block communication at excitatory and inhibitory synapses. I utilized a Cre/loxP genetic approach to conditionally remove the vesicular GABA transporter (VGAT) or vesicular glutamate transporter (VGLUT2) at all major synapses in the cerebellum. My preliminary data shows that the only way I can induce dystonia is to block VGLUT2 at climbing fiber to Purkinje cell connections. Climbing fibers coordinate movement, correct motor errors, and facilitate motor learning. Now, I would like to expand on this by testing the hypothesis that loss of climbing fiber signaling causes dystonia by damaging cerebellar communication at a particular time and in a particular manner. In my first aim, I will trace the path of a typical signal through the cerebellu after silencing climbing fiber synapses. I will delineate how loss of climbing fiber communication leads to dystonia by recording neurons during dystonic movements. Then, by microinfusing a neural blocker in vivo, I will suppress dystonia by preventing erroneous commands from leaving the cerebellum. Next, I will test if dystonia during childhood is triggered by the same mechanism as adult. Thus, in my second aim I will test if blocking developing climbing fibers has the same pathogenic outcome to blocking them in adults. For this, I modified my approach so that I could silence climbing fibers with temporal precision to pinpoint when their loss causes dystonia. I will measure circuit wiring, muscle contractions, and neuronal activity in behaving mice. The data that I generate could have a major influence on treatment because the cerebellum could be a new target for pharmacological and deep brain stimulation therapy in dystonia. RELEVANCE TO PUBLIC HEALTH: Cerebellar dysfunction may be a primary problem in dystonia. But how it instigates the disease is still unknown. My goal is to test if cerebellar miscommunication triggers dystonia, and to determine how these defects impact movement. Solving this problem could provide new opportunities to treat dystonia by targeting the cerebellum with drugs and stimulation.

PUBLIC HEALTH RELEVANCE: Dystonia causes painful muscle contractions because communication falls apart in the motor system; and although the basal ganglia are thought to be the main culprit, the cerebellum has recently emerged as another area that might cause major problems in the disease. My goal in this proposal is to test if obstructing cerebellar communication triggers dystonia, and if it does, test how the defective signals destroy critical motor commands. Addressing this problem could uncover new brain targets for pharmacological and deep brain stimulation therapy and thus provide novel treatment opportunities.