Proposed roles of KCNQ2 Channels in Respiratory Homeostasis

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT KCNQ channels are key determinants of neuronal activity, and recent clinical evidence identifies mutations in KCNQ2 as a cause of neonatal epileptic encephalopathy. Most variants associated with neonatal epileptic encephalopathy are Loss-of-Function.However, recent work also identified a recurrent KCNQ2 Gain-of-Function mutation (R201C) in patients with neonatal onset encephalopathy. Patients with both KCNQ2 Loss- and Gain- of-Function mutations exhibit respiratory dysfunction including central hypoventilation syndrome, a condition thought to result from loss of respiratory chemoreception, i.e., the mechanism by which the brain regulates breathing in response to CO2/H+. The retrotrapezoid nucleus (RTN) is an important chemoreceptor region, and we have shown previously that KCNQ channels regulate basal activity and neurotransmitter modulation of RTN chemoreceptors. Therefore, I hypothesize that KCNQ2 channels are the principal KCNQ subunits that control activity of RTN chemoreceptors. Ipropose that KNCQ2 Gain-of-Functionwill hyperpolarize RTNchemoreceptors and eliminate their contribution to the drive to breathe, whereas KCNQ2 Loss-of-Function mutations will destabilize RTN chemoreceptor activity and disrupt modulation by neurotransmitters, thus also contributing to unstable breathing. Additionally, I will also test whether KCNQ2 dysfunction affects not only the RTN but the respiratory control circuit in general including other chemoreceptors, inspiratory rhythmogenic pre-Bötzinger complex neurons, and output respiratory motor neurons. Objectives of this study are to investigate, from the cellular to system level, contributions of KCNQ2 channels to chemoreceptorfunction and respiratory control. The two Specific Aims of this project are: 1) determine cellular effects of KCNQ2 on respiratory chemoreception, inspiratory rhythmgeneration and motor output and 2) determine the essential role of KCNQ2 channels in control of breathing. The rationale for the proposed research is that by understandingwhether and howKCNQ2 channels regulate neuronal activity across multiple levels of the respiratory circuit, and respiratory behavior, I will lay a foundation for development of treatments for respiratory problems like apnea and central hypoventilation syndrome.