SEROTONIN REGULATION OF BASAL GANGLIA NEUROPEPTIDES

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This research will determine the role of serotonin transmission in the regulation of neuropeptide gene expression in the basal ganglia. Specifically, we will test hypothesis that: Serotonin transmission provides regulatory control over neuropeptide nMRA expression within the basal ganglia via multiple receptor subtypes. Although this regulation may only provide slight adjustments to gene expression under normal conditions in the adult brain, serotonin may exert larger influences during development, in response to dopamine depletion, or during glutamate-induced excitotoxic damage. The following specific aims will determine: 1. Serotonin Receptor-Mediated Regulation of Gene Expression in the Normal Adult Basal Ganglia. Multiple serotonin receptors subtypes may differentially influence gene expression in the basal ganglia. Northern analysis and in situ hybridization methods will be utilized to determine which serotonin receptors are linked to transcriptional regulation of preprotachykinin and preproenkephalin genes expressed in the striatum. 2. Serotonin Influences on Basal Ganglia Gene Expression during Development. Serotonin afferent to the forebrain appear early during development and have been postulated to play a morphogenic role in brain maturation. During embryonic and early postnatal time periods, serotonin transmission will be altered and specific receptors subtypes will be identified that influence the development of neuropeptide gene expression patterns in the basal ganglia. 3. Serotonin Influences on Basal Ganglia Gene Expression during Altered Dopamine Transmission. Serotonin may increase its influence on basal ganglia gene expression in response to altered dopamine neurotransmission. Therefore, experiments will determine the role of serotonin and its receptors in regulating neuropeptide gene expression following manipulation of dopamine neurotransmission in both neonatal and adult brains. 4. Serotonin Mechanisms That Affect Gene Expression during Glutamate Neurotransmission and Excitotoxic Damage of the Basal Ganglia. Serotonin may modulate the effects of glutamate excitatory neurotransmission in the basal ganglia, as well as mediate glutamate receptor induced excitotoxicity. Experiments will determine how serotonin contributes to the regulation of basal ganglia gene expression following abnormal glutamate receptor stimulation. Completion of these studies will increase our understanding of how serotonin transmission influences gene expression patterns in the normal developing and adult basal ganglia; as well as in response to changes in dopamine and glutamate neurotransmission. Such information will increase our awareness of serotonin as a major afferent regulator of basal ganglia function and lead to the development of serotonin-based therapies to treat basal ganglia disease.