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, including reward-conditioned learning. Drug-induced plasticity within the ventral 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 a variety of cellular pathways that signal to the nucleus. Thus, in addition to their rapid behavioral 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, glutamate, and serotonin 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 """"""""target genes"""""""" such as the prodynorphin and proenkephalin genes within striatal neurons. We have also investigated the precise cell types in which transcription factors are altered by different stimuli. During the past year, the section continued its investigations into the complex interactions of neurotransmitters and of the cyclic AMP and Ca2+ signaling pathways in regulating transcription factors in striatal neurons. However, a major recent focus has been the identification of additional target genes activated by dopamine, presumably via transcription factor CREB. We have identified more than 30 dopamine regulated genes of which at least 10 are not represented in current EST data bases. 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. As the research progresses, transgenic and knockout mice will be made as is appropriate. 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.
