The targeting of neurotransmitter receptors to synapses is necessary for efficient synaptic transmission and the dynamic regulation of this process plays an important role in the regulation of synaptic plasticity in the brain. Studies in developmental biology and in neurobiology have demonstrated that a protein-protein interaction motif called a PDZ domain is critical for the proper localization of proteins to cell-cell contacts. We have identified several PDZ domain-containing proteins that specifically interact with AMPA receptors, the major excitatory neurotransmitter receptors in the central nervous system, and are involved in the regulation of the membrane trafficking and synaptic localization of these receptors. Several of these proteins, including GRIP1 and 2 (Glutamate Receptor Interacting Proteins) and PICK1 (Protein Interactor with C Kinase), specifically interact with the C-terminal domains of the AMPA receptor GluR 2, 3 and 4c subunits. In addition, we have found that these interactions can be dynamically regulated by protein phosphorylation of the receptor subunits. In this research proposal we plan to further characterize the structure and function of PICK1 and GRIP 1/2 and determine their role in the membrane trafficking of AMPA receptors and synaptic plasticity in the brain. Specifically, we will identify proteins that interact with PICK1 and GRIP1/2 to form PDZ domain-based receptor complexes in neurons. In addition, we will examine the dynamic regulation of the interaction of AMPA receptors with PICK1 and GRIP1 by phosphorylation and the role of this modulation in synaptic plasticity. Moreover, we will analyze the cellular and electrophysiological phenotypes of PICK1 and GRIP 1/2 knockout mice and a phosphorylation site mutant knock-in mouse. Finally, we will analyze any behavioral phenotypes of the knockout and knock-in mice to determine the role of these regulatory mechanisms in higher brain processes such as learning and memory. These studies will elucidate basic mechanisms that regulate synaptic transmission, synaptic plasticity and animal behavior. This research has broad relevance for many neurological and psychiatric diseases. Dysfunction of synaptic transmission and synaptic plasticity is thought to be the underlying basis of many neuropsychiatric disorders. For example, hyper-activation of excitatory synaptic transmission is critical for many neurodegenerative diseases while hypo-activation of synaptic function may be involved in schizophrenia. Moreover, synaptic plasticity mechanisms are thought to be critical in many abnormal nervous system processes such as the generation of neuropathic pain and drug addiction. The elucidation of the basic mechanisms underlying the regulation of synaptic transmission may provide novel therapeutic approaches to these disorders.