Control of Motor Systems by Cotransmitters

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DESCRIPTION (provided by applicant): The broad, long-term objective of this research is to understand how neurotransmitter systems control motor activity. The present study will address the mechanistic and functional consequences of signaling by neurons that contain multiple neurotransmitters. It will utilize an experimentally favorable model in which it is possible to identify specific neurons that exhibit a particular transmitter phenotype and to determine the contribution of those neurons to the generation of complex motor patterns. Experiments conducted to date have 1) localized the neurons that contain GABA and dopamine (DA) in Aplysia, 2) demonstrated that the overlap, or colocalization, of these major neurotransmitter systems occurs in only five neurons, all of which participate in the central pattern generator (CPG) circuit that controls feeding, and 3) localized GABA-DA coexistence to identified interneurons that can specify the functional configuration of this multifunctional CPG. Methods integrating neurophysiology, neuroanatomy, and pharmacology will test the central hypothesis of this study: GABA-DA interneurons that are intrinsic to a multifunctional CPG circuit can specify functional motor patterns via modulatory signaling. The proposed experiments address three specific aims that test this hypothesis: 1) determine the contributions of DA and GABA to rapid and slow synaptic signaling by the neurons in which they are colocalized, 2) explore the roles of colocalized DA and GABA in the regulation of multiple forms of synaptic plasticity that these interneurons display, and 3) determine the respective contributions of colocalized DA and GABA to the modulation of intrinsic membrane properties of postsynaptic motor neurons. These studies promise to lead to insights and principles that will have applicability to motor control in more complex brains, including the human central nervous system. In view of the pivotal role of dopaminergic and GABAergic neurotransmitter systems in our present understanding of major neurological movement disorders, these principles should also inform efforts to develop therapeutic and treatment strategies. The developmental objectives of this project will enable the PI to continue his efforts to acquire competitive research support. In view of positive evaluations of recent proposals, it is anticipated that this objective will be achieved during this grant period. Public Health Relevance: Several major neurological movement disorders, such as Parkinson's Disease and Huntington's Disease, are currently attributed to the malfunctioning or imbalance of specific brain pathways. This project will examine the contributions of brain cells that contain specific signaling molecules, or neurotransmitters, to the control of movement. This investigation will increase our understanding of how brain circuits control motor behavior and how major movement disorders result when these circuits are compromised.