The Molecular Plasticity Section is interested in how neurotransmitters, most importantly dopamine and glutamate, and pharmacologic agents, such as amphetamine, cocaine, and direct dopamine agonists and antagonists produce long-term changes in the functional properties of striatal neurons by regulating gene expression. In addition to its well known role in motor control, the striatum plays a key role in the formation of important types of implicit memory. Drug-induced plasticity within the striatum is central to the pathogenesis of addictive disorders. In addition, striatal plasticity plays a key role in the pathophysiology of Parkinson?s disease- and in limiting the utility of long-term dopamine replacement therapy; striatal plasticity may also be related to the actions (both therapeutic and unwanted) of antipsychotic drugs. Activation of dopamine and glutamate receptors expressed on striatal neurons leads to the activation of multiple intracellular pathways that signal to the nucleus. Thus, in addition to their rapid physiological effects, activation of these receptors produce slower post-receptor adaptations, including regulation of gene expression, that ultimately alter neuronal function and therefore the behavior of neuronal circuits. The section is focused on the intracellular signaling pathways that convert stimulation of dopamine andglutamate receptors into patterns of altered gene expression. We have studied the mechanisms leading to activation of the CREB and AP- 1 families of transcription factors, and have demonstrated the relationship between CREB activation and the expression of known """"""""target genes"""""""" such as the prodynorphin and proenkephalin genes within striatal neurons. Using differential display PCR we have identified an additional 30 target genes activated by dopamine, presumably via transcription factor CREB. We are pursuing the function of several of these genes, by both molecular and biochemical means as well as by patch clamp physiology in primary striatal cultures and in striatal slices. The ultimate goals of the research are to understand in detail the molecular mechanisms underlying alterations in striatal function in addictive disorders and Parkinson's disease.
