Receptor-mediated gene expression in matured CNS neurons remains a hot topic in elucidating molecular mechanisms for the development of neuroplasticity. As a key structure of the basal ganglia, the striatum is among the major central sites for investigating such gene expression aimed to unravel striatal mechanisms underlying a variety of mental illnesses (psychiatric and cognitive disorders). Metabotropic glutamate receptors (mGluRs) are densely expressed in the striatal projection neurons. From studies conducted in the last period, we have established that Ca2+ -Iinked group I mGluRs play a profound role in regulating opioid peptide gene expression (prodynorphin and proenkephalin) in the rat striatum. In the effort of identifying intracellular signaling pathways transducing group I mGluR signals to the gene expression, we recently found that activation of group I receptors activates mitogen-activated protein kinases (MAPKs). As an information superhighway between the surface membrane and the nucleus, the MAPK pathway therefore likely couples group I mGluRs to gene expression. In this continuation proposal, a series of experiments was proposed to evaluate an overarching hypothesis that group I mGluRs activate MAPK cascades to facilitate opioid gene expression in striatal neurons. Using multidisciplinary approaches, this hypothesis will be tested both in vivo and in vitro n striata neurons in four general experiments: (1) define the role of group I receptors in the regulation of MAPKs by characterizing group I I mGluR-regulated phosphorylation of a major MAPK subclass, extracellular signal-regulated kinase 1 and 2 (ERKI/2), in a I well-characterized in vivo rat model, (2) differentiate the relative importance of the two group I subtypes, mGluR1 and I mGluR5, in this event using the subtype-selective agonists/antagonists, antisense oligos and mutant mice (mGluR1 or 5l knockouts) in vivo, (3) identify signaling pathways transducing group I mGluR signals to MAPK/ERK by evaluating roles of Ca 2+ signals and protein kinases (CaMKII, PI3-kinase, PKC, and tyrosine kinases) in our primary striatal neuronal culture model with selective inhibitors, antisense oligos and silencer siRNAs, and (4) define physiological roles of group I mGluRactivated MAPK/ERK cascades in the regulation of striatal gene expression via evaluating the importance of the two transcription factor targets of MAPK/ERK, Elk-1 and CREB, for group I/ERK-sensitive prodynorphin and proenkephalin gene expression in vivo and in vitro. Accomplishment of this project will provide a new interpretation of receptor and signal transduction mechanisms underlying inducible gene expression in matured CNS neurons. Since inducible gene expression is conceived to be an important component of the development of neuroplasticity, data from this project can ultimately contribute to the development of novel pharmacotherapies, by targeting group ImGluRs and MAPK cascades, for the treatment of various mental illnesses resulted from striatal dysfunctions.
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