The striatum is involved in pervasive motor and psychiatric disorders such as Parkinsons's and Huntington's disease, schizophrenia, dystonia, Tourette syndrome, and attention deficit and obsessive compulsive disorders. It has been recently recognized that a subpopulation of fast-spiking GABAergic interneurons is a critical element of striatal circuitry. These interneurons provide the major source of inhibition within the striatum. They powerfully inhibit large numbers of striatal efferent neurons and mediate their feed forward inhibition by cortical inputs. These GABAergic interneurons have unique molecular properties among striatal neurons, in particular a high level of expression of GAD67, parvalbumin, and the shaw-like potassium channel KV3.1. In addition, they are coupled electrotonically by GAP junctions made of connexin-36. They are regulated by nigrostriatal dopaminergic neurons, and depend on BDNF for their development. We will use a multidisciplinary approach combining molecular, morphological and electrophysiological techniques in genetically altered mice to elucidate the role of connexin-36, Kv3.1, dopamine and BDNF in the regulation of the molecular and functional properties of these fast-spiking GABAergic interneurons. We will measure Parvalbumin, GAD67, Kv3.1, connexin-36, and their mRNA by immunohistochemistry and single cell semi-quantitative in situ hybridization histochemistry, respectively. Changes in electrophysioiogical properties (action potential characteristics, spike trains, electrotonic coupling and cortical inputs) of the striatal fast-spiking GABAergic interneurons will be analyzed in striatal slices. These experiments will be done in mice lacking intrinsic molecules that may be critical for the functional properties of the fast-spiking GABAergic interneurons, specifically connexin-36 and Kv3.1, and in mice with alteration in extrinsic factors known to alter the function of these interneurons, specifically dopamine and Brain Derived Growth Factor (BDNF). These studies will provide basic information on the mechanisms involved in the maturation of a crucial population of striatal GABAerglc neurons and provide new cues for striatal pathologies.
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