The role of glutamate receptors in compulsive and perseverative behavior

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The dorsolateral striatum integrates convergent cortical and thalamic input to control action initiation and termination Multiple disorders including obsessive compulsive disorder (OCD), autism spectrum disorders (ASDs), and Tourette syndrome have altered function or maladaptive rearrangements of triatal circuits, resulting in aberrant perseverative and repetitive behaviors. The spiny projection neurons (SPNs) make up approximately 90% of all the neurons in the striatum and are strictly divided by their incorporation and contribution to the direct pathway (important for action initiation) and the indirect pathway (involved in action termination In particular, two glutamate receptor types, Group 1 metabotropic glutamate receptors (mGluRs) and kainate receptors (KARs) are important in regulating activity of both the direct pathway SPNs (dSPNs) and indirect pathway neurons (iSPNs). Each of these receptors have multiple overlapping cellular functions, yet it remains unclear how each receptor type contributes precisely to establishing and modulating synapses, and affecting excitability of SPNs in the dorsolateral striatum. We have developed novel mice in which each of these receptors are ablated conditionally in either dSPN or iSPNs. These mice demonstrate interesting behavioral phenotypes that suggest divergent and dichotomous roles for each glutamate receptor type in the striatum. In this proposal we will take a comprehensive approach to map the cellular to circuit function of mGluRs and KARs, and determine how each of them has distinct roles in regulating striatal output. The goal is to determine how each of the receptor types regulates synaptic and intrinsic properties of the SPNs, and how contribute to the balanced output of this circuit that is vital to appropriate behavioral actions. Thus, in the first aim we will determine the cellular roles of mGluRs and KARs in each of the SPN types. In the second aim we will determine how each of the glutamate receptor types contributes to the balanced activity of the striatal circuit. Finally, in the third aim we will use in vivo imaging of SPN activity during the initiation of motor and habitual actions to determine whether imbalanced SPN function is evident during aberrant and maladaptive behaviors when glutamate receptors are ablated in SPNs. Together these studies will take a comprehensive and integrative approach to determine the cellular and circuit roles played by glutamate receptors in regulating striatal circuits, and will inform us about how these receptors contribute to disorders with maladaptive and compulsive behaviors.