Activity-dependent changes in excitatory synaptic function and structure importantly contribute to the modifications in neural circuitry that underli many forms of adaptive and pathological experience-dependent plasticity. Indeed, maladaptive or dysfunctional synaptic plasticity has been proposed to play a critical role in a variety of brai disorders including drug addiction. Thus understanding the molecular mechanisms contributing to synaptic and experience-dependent plasticity will provide important insights into normal circuit function as well as the maladaptive circuit modifications that underlie brain disorders. The mammalian brain expresses several different forms of synaptic plasticity with distinct triggering and expression mechanisms. Several of these, which have been specifically implicated in disease states, are triggered by activation of group I metabotropic glutamate receptors (mGluRs). Like most G-protein coupled receptors, group I mGluRs are tightly regulated by a macromolecular protein complex, a key component of which is the scaffolding protein Homer. Homer proteins regulate the expression and function of group I mGluRs at multiple levels including targeting, surface expression, clustering, and physical linkage to other synaptic and subsynaptic complexes. In this collaborative project involving a US laboratory at Stanford University and an Indian laboratory at the Indian Institute of Science Education and Research in Mohali , experiments will be performed to address the hypothesis that Homers regulate the function of the specific group I mGluR, mGluR5, in an isoform- and cell type-specific manner. Specifically, the functional significance of Homer in regulating mGluR5 trafficking and mGluR5-triggered synaptic plasticity in hippocampal CA1 pyramidal cells and nucleus accumbens medium spiny neurons using molecular manipulations combined with electrophysiological and imaging assays will be explored. The long-term goal of this project is to test the roles of Homer modulation of mGluR5 signaling in drug-evoked forms of behavioral plasticity of relevance to the development and maintenance of addiction. The results will open up new, innovative areas of research on the brain mechanisms underlying brain disorders such as addiction and will provide findings that are critical for the development of more effective treatments. Relevance Drug addiction involves long-lasting modification of the communication between nerve cells at their physical connections, which are termed synapses, in certain key brain areas. This project will use sophisticated experimental techniques to elucidate some of the key molecular mechanisms by which these modifications of synapses occur. The information that will be collected is essential for the development of more effective treatments for addiction and other related brain disorders. PUBLIC HEALTH RELEVANCE: Drug addiction involves long-lasting modification of the communication between nerve cells at their physical connections, which are termed synapses, in certain key brain areas. This project will use sophisticated experimental techniques to elucidate some of the key molecular mechanisms by which these modifications of synapses occur. The information that will be collected is essential for the development of more effective treatments for addiction and other related brain disorders.