Developmental Regulation of Potassium Channels in Hypothalamic Neurons Governing Energy Homeostasis

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PROJECT SUMMARY/ABSTRACT The long-term goal of this work is to understand how metabolic signaling can alter the functional development of energy homeostasis pathways through the modulation of specific ion channels in hypothalamic neurons. The hypothalamus is a brain region that mediates the regulation of critical metabolic processes throughout the body. Specialized hypothalamic neurons can integrate the homeostatic balance between food intake and energy expenditure via peripheral signals, a process that may become dysregulated in obesity and other metabolic disorders. Evidence indicates that the function of Kv1.3, a voltage-gated potassium channel governing neuronal excitability and resting membrane potential, can be modulated by circulating peripheral signals such as insulin, although the role of this modulation in the early development of hypothalamic circuits remains unclear. The central hypothesis of this proposal is that insulin modulates the developmental function of Kv1.3 in hypothalamic neurons governing energy homeostasis. The central hypothesis will be tested with the following specific aims: (1) identify the developmental colocalization of Kv1.3 and the insulin receptor (IR) in specific hypothalamic nuclei governing energy homeostasis, (2) define how hypothalamic Kv1.3 channels are functionally modulated by insulin during development, and (3) determine the role of heteromultimeric Kv1 complexes in channel regulation of the developing hypothalamus. In order to achieve the experimental objectives, immunofluorescence will be used to identify Kv1.3 and IR protein at different developmental stages in specific hypothalamic nuclei involved in metabolic function. To test the hypothesis that insulin regulates neuronal activity via suppression of Kv1.3, brain slices of the avian hypothalamus will be exposed to exogenous insulin and changes in ion channel function will be recorded using electrophysiological techniques. Subsequently, in ovo hormone application will be used to determine the long-term effect of insulin exposure on the electrophysiological function of Kv1.3 in hypothalamic neurons at critical embryological time points. The physiological effects of Kv1 channel heteromultimerization on the insulin-sensitive function of Kv1.3 channels in hypothalamic neurons will also be explored. This proposal will be the first to elucidate the developmental role of insulin exposure on Kv1.3 channel function in hypothalamic neurons governing energy homeostasis. Examining the developmental regulation of Kv1.3 in this embryonic system will provide new insight fundamental to understanding the early patterning of hypothalamic circuits and may provide further evidence targeting these potassium channels in the pharmaceutical intervention of metabolic disorders such as diabetes and obesity.