This proposal is a competing continuation application for an Independent Scientist Award (K02). Such an award will provide the scientific freedom and institutional support that are required to pursue my career goal of elucidating the cellular and biochemical mechanisms underlying synaptic plasticity in the mammalian brain. Long-lasting, activity-dependent changes in the strength of synaptic transmission play a critical role in the development of neural circuits and in the storage of information. Such changes occur in brain regions that are involved in the pathophysiology of many neuropsychiatric disorders including schizophrenia, drug addiction and Alzheimer's disease. Thus the proposed examination of synaptic plasticity in several different brain regions will lead to a better understanding of the etiology of brain disorders and to the development of drugs that alleviate psychiatric symptoms and prevent the deterioration of cognitive function that accompanies mental illness, drug addiction and aging. The most well-understood models of synaptic plasticity are the forms of long-term potentiation (LTP) and long-term depression (LTD) that occur in the hippocampus. An extensive series of experiments will examine some of the critical issues concerning the mechanisms responsible for LTP and LTD. The role of changes in postsynaptic calcium concentration and the modification of glutamate receptor function by protein kinases and protein phosphatases will be a major focus. Via collaborations, I will have the opportunity to interact with and learn from preeminent investigators studying these issues. I will also learn about techniques and approaches not presently used in my laboratory. A second project will examine the mechanisms of synaptic plasticity in the nucleus accumbens, a region of brain implicated in drug abuse and addiction. The basic mechanisms of LTP and LTD in this region will be defined and the modulation of synaptic plasticity by dopamine and the psychostimulants, cocaine and amphetamine, will be examined. This represents a new area of research and provides an opportunity for learning about and contributing to the current understanding of the biological basis of drug abuse and addiction. A final project will examine the development and mechanisms of synaptic plasticity at thalamocortical synapses in somatosensory cortex. These experiments will provide important information about the mechanisms that control the development of cortical circuitry and will expand my potential to make significant contributions to an area of research with broad clinical implications.
