In Vivo Striatal Fast Spiking Interneuron Suppression Using Optogenetic Techniques

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Michigan
Investigators Name
Berke, Joshua, PhD

Striatal GABAergic microcircuitry likely plays a key role in the pathophysiology of Tourette syndrome (TS). Humans with TS have a specific deficiency in GABAergic striatal fast-spiking interneurons (FSIs), which powerfully inhibit striatal projection neurons. Animal experiments have found that blockade of striatal GABA receptors provokes tic-like movements. These data suggest that FSIs play a critical role in the pathophysiology of TS. To test this hypothesis, we are using novel optogenetic and pharmacological techniques to selectively silence striatal FSIs in awake, freely behaving mice. In one set of experiments we use a Cre/lox approach to express the light-sensitive chloride pump halorhodop-sin specifically in FSIs. In the complementary experiments we selectively shut down excitatory input to FSIs by local infusion of drugs that block calcium-permeable AMPA receptors. In both cases we monitor activity patterns in the surrounding neuronal network using high-density recording methods, and also monitor the corresponding behavioral effects. We find that FSI suppression causes contralateral abnormal movements, and we are currently working to understand the specific relationships between these dyskinesias and altered striatal network activity. Joshua D. Berke, Ph.D. , Daniel Leventhal, M.D., Ph.D. University of Michigan, Ann Arbor, MI Award: $40,000 (2nd Year) Commentary: Recent evidence suggests that a deficiency of a type of nerve cell (called “fast spiking interneurons” or FSIs) in a specific brain region (the striatum) is associated with Tourette syndrome (TS). These investigators will use new techniques to reduce the activity of FSIs in normal mice and will determine the effect that this has on nearby nerve cells and movement. A better understanding of the role of FSIs in the brain may enable the development of novel therapies for TS and other neurological conditions. Tourette Association of America Inc. – Research Grant Award 2011-2012