The neostriatum is directly involved in the pathophysiology of several clinically significant neurological and neuropsychiatric conditions. A crucially important question is to understand how dopamine regulates the function of this brain area. Recently, we conducted preliminary experiments to examine the possible roles of newly discovered GABAergic interneurons in the dopaminergic control of the neostriatum. Surprisingly, we found that cell-type specific neurotoxic lesion of tyrosine hydroxylase expressing GABAergic interneurons (THINs) dramatically alters the behavioral response of mice to the administration of the psychostimulant amphetamine. These results suggest that despite their very small population size, THINs have a crucial role in regulating the dopaminergic control of the neostriatum and that of striatal-dependent behavior. The proposal evaluates the feasibility of a new avenue of investigation into the functioning of THINs and their role in the dopaminergic control of behavior. The proposal addresses the following aims. First, we will develop and optimize techniques that will enable the reversible and effective inactivation of THINs in transgenic mice. Second, we will test if transient inactivation of THINs using these tools recapitulates the results of the neurotoxic lesion experiments. Preliminary results indicate that partial, transient pharmacogenetic inhibition can qualitatively reproduce the phenomena observed with irreversible methods. Next, we will test the hypothesis that reversible inactivation of THINs enhances the effect of amphetamine resulting in long- lasting changes in the striatal circuitry, in particular the excitatory cortical inputs to projection neurons. Investigation of the function of THINs may lead to significant breakthroughs in elucidating the mechanism of action of psychostimulants and more generally numerous problems of dopaminergic signaling including the control of movement, learning and reinforcement as well as the processes that contribute to the development of pathological conditions ranging from Parkinson's disease to drug abuse.
Numerous important neurological and psychiatric disorders including Parkinson's and Huntington's diseases, schizophrenia, Tourette's syndrome, obsessive compulsive disorder arise from pathological conditions of the neostriatum. Several of these are directly or indirectly linked to striatal interneurons in this structure, yet critically important issues about the role of these interneurons remains unanswered. We have recently discovered that these interneurons form a previously unknown, large and complex circuitry. However, many of the participating cell types represent extremely small cell populations that call into question their importance for the operation of the basal ganglia. Most recently, we observed that a class of very rare novel GABAergic interneurons exerts an extremely powerful effect on the dopaminergic modulation of behavior. If confirmed, this finding could be of revolutionary significance for the understanding of striatal interneurons and the mechanism of action of dopamine. The proposal will examine the feasibility to mechanistically studying the role of these interneurons in striatally controlled behavior. These experiments may ultimately lead to improved methods for pharmacological or other treatment modalities in the management of common neurological disorders.
