Current Efforts

The primary focus of research in our laboratory is to develop a detailed understanding of the cellular and molecular mechanisms involved in regulating chemical and electrical signaling in the central nervous system (CNS). Such changes in neuronal function are likely to play important roles in all normal physiological processes in the brain and are critical for development of a variety of brain diseases, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, epilepsy, drug dependence and other neurological and psychiatric disorders. We are especially interested in understanding how signaling is regulated by regulation of ion channels, transporters, and receptors in identified neuronal circuits that are important for these human neurological and psychiatric disorders. This is a highly multidisciplinary endeavor and we employ a broad range of techniques including electrophysiology, biochemistry, imaging, anatomy, and molecular biology techniques. Since our ultimate goal is to understand the impact of cellular and molecular changes to changes in intact neuronal networks and animal behavior that impact CNS disorders, we also employ a range of techniques in behavioral and systems neuroscience. By developing this range of understanding, we hope to develop new strategies for treating neurological and psychiatric disorders. Our current research is especially focused on development of novel treatment strategies for schizophrenia, severe anxiety disorders, and Parkinson’s disease. Also, we have increasing interests in drug addiction and Alzheimer’s disease. In each of these areas, recent basic and clinical studies are shedding light on new approaches to develop novel treatment strategies.

While our interests in neuromodulation are broad, we have focused primary attention on the physiological roles of a family of G protein-coupled glutamate receptors termed metabotropic glutamate receptors (mGluRs). At a circuit level, we have placed a major emphasis on the roles of mGluRs in regulating transmission through the hippocampal formation and through basal ganglia circuits involved in regulation of motor function and processing of information flow to the cortex. In addition to understanding the roles of mGluRs and other G protein-coupled receptor (GPCRs) in regulating transmission through these circuits, we are placing a significant effort on understanding the precise molecular mechanisms by which GPCRs and signaling cascades activated by these receptors modulate cell excitability and synaptic transmission. These studies are largely focused on identifying protein kinases and phosphatases involved in specific effects, substrates and phosphorylation sites involved, and the impact of such posttranslational changes on protein function. Finally, we are making rapid progress understanding the impact of these changes at a behavioral level. These studies are having a major impact on our understanding of the cellular and systems level mechanisms involved in regulation of complex aspects of animal behavior and disorders of the central nervous system.

Our basic science studies are revealing a number of key regulatory proteins that have exciting potential as novel drug targets for treatment of serious psychiatric and neurological disorders. In addition to pursuing the basic research needed to identify these novel drug targets, we are directly involved in taking these findings to the next level by pursuing early stage drug discovery efforts. We have access to libraries of over 1 million novel small molecules with drug-like properties. In addition, we have established the infrastructure needed for high-throughput screening these molecules for unique compounds that have potential for development into novel drugs. Thus, as specific ion channels, neurotransmitter transporters, and other potential drug targets are identified, we move aggressively to identify novel ligands for these targets to help us further understand the function of these proteins in neuronal circuits. By initiating early stage drug discovery programs, we are making exciting advances that could lead to novel treatments for schizophrenia, Parkinson’s disease, and other CNS disorders.