Paul D. Walker - US grants

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.

DESCRIPTION: (Verbatim from the Applicant's Abstract) Attempts to develop new and effective treatments for movement disorders such as Parkinson's disease have been hampered by an insufficient knowledge of how basal ganglia receptor systems adapt to the consequences of dopamine depletion. This research focuses on determining the role of upregulated serotonin 2A receptors, which we hypothesize provide a mechanism for serotonin to exert greater control over basal ganglia transmission and locomotor function under conditions of dopamine depletion. Our preliminary studies indicate that the target of the serotonin 2A receptor mechanism is the DIRECT striatonigral pathway which utilizes tachykinin neuropeptides colocalized with GABA. New experiments of this application will test the central hypothesis that: upregulated serotonin 2A receptor signaling provides a mechanism for serotonin to enhance striatonigral transmission under conditions of dopamine depletion which influences basal ganglia function and animal behavior. In Specific Aim 1, we will determine the functional consequences of an upregulated serotonin 2A receptor system on serotonin signal transduction within the dopamine depleted striatum by measuring serotonin 2A receptor binding, its linkage to phosphoinositol hydrolysis, its modulation of striatal membrane excitability, and its ability to trans-synaptically regulate striatal tachykinin and GABA expression. In Specific Aim 2, we will determine if tachykinin striatonigral neurons react to the stimulation of upregulated serotonin 2A receptors in the dopamine depleted animal by increasing tachykinin and GABA transmission in the substantia nigra. We will also study the impact of this regulation on locomotor behavior. Finally, in Specific Aim 3, we will determine how an upregulated serotonin 2A receptor system influences the ability of the striatonigral system to regulate basal ganglia dopamine and GABA metabolism, and how these systems influence behavioral recovery of the dopamine depleted animal. Information obtained from these studies will contribute to a better understanding of basal ganglia function and may change how serotonin pathways are considered when designing new pharmacological strategies for diseases which affect dopamine transmission.