CELLULAR PHYSIOLOGY OF EPILEPSY-ASSOCIATED KCNQ2 and KCNQ3 CHANNELS

KCNQ2/3通道已成为新生儿大脑兴奋性的重要调节因素，因为无论是失去还是获得- 在新生儿和婴儿癫痫患者中发现了功能缺失的KCNQ2和KCNQ3突变 脑病。因此，对神经元KCNQ2/3通道的功能有了更深入的了解 大脑对于开发治疗新生儿癫痫的新疗法至关重要。在本供资期间 我们在确定KCNQ2和KCNQ3通道在调控中的不同作用方面取得了进展 锥体神经元的兴奋性和介导多膜电导(M电流、中电流和慢电流) AHP)。在此应用程序中，我们建议进行实验，以解决有关 前脑KCNQ2/3钾通道的功能和特性。例如，与 KCNQ2/3通道在兴奋性神经元中的作用，这些通道在 中间神经元仍不清楚。这是我们知识中的一个主要缺口，因为中间神经元在 塑造神经元群体的活动，促进兴奋性突触回路的发展。 KCNQ2/3通道在发育早期表达，当时中间神经元还没有完全获得 一系列独特的钾通道，增加了KCNQ2/3通道控制中间神经元的可能性 处于早期发展阶段的财产。此外，有可能的是，兴奋性的增加 中间神经元是KCNQ2/3功能获得突变体过度兴奋性表型的罪魁祸首 癫痫性脑病。因此，阐明KCNQ2/3通道在神经元间兴奋性中的作用，以及 探索已知的功能获得性KCNQ2/3突变的影响，将为大脑皮质提供新的见解 健康和疾病中的生理学。为此，我们将：(I)确定KCNQ2/3通道在 未成熟的PV+和SST+中间神经元使用细胞类型特定遗传学，(Ii)确定是否丢失 PV+/SST+中间神经元的KCNQ2/3活性转化为其种群节律的变化 使用新的成像方法的体外和体内活性，以及(Iii)确定是否获得- KCNQ2/3功能突变导致神经元间兴奋性低下。拟议的研究将使 对我们更广泛地理解KCNQ2/3通道如何控制神经元兴奋性做出了重大贡献， 为儿童癫痫等神经系统疾病的防治奠定基础。

KCNQ2/3 channels have emerged as essential regulators of neonatal brain excitability as both loss- and gain- of-function KCNQ2 and KCNQ3 mutations have been identified in patients with neonatal and infantile epileptic encephalopathy. Therefore, an improved understanding of the function of neuronal KCNQ2/3 channels in the brain is paramount for the development of new therapeutics for neonatal epilepsy. In the current funding period we have made progress in determining the differential roles of KCNQ2 and KCNQ3 channels in controlling pyramidal neuron excitability and in mediating multiple membrane conductances (M-current, medium and slow AHP). In this application, we propose experiments to tackle important outstanding questions regarding the function and properties of KCNQ2/3 potassium channels in the forebrain. For instance and in contrast to the wealth of knowledge on the role of KCNQ2/3 channels in excitatory neurons, the roles of these channels in interneurons is still unclear. This is a major gap in our knowledge as interneurons play a critical function in shaping the activity of neuronal populations and in promoting the development of excitatory synaptic circuits. KCNQ2/3 channels are expressed early in development when interneurons have not yet fully acquired their clade of unique potassium channels, raising the possibility that KCNQ2/3 channels might control interneuron properties at earlier developmental stages. Furthermore, it is possible that an increase in the excitability of interneurons is the culprit of the hyperexcitability phenotype of the gain-of-function KCNQ2/3 mutants in epileptic encephalopathy. Thus, elucidating the role of KCNQ2/3 channels in interneuron excitability, and exploring the effects of the known gain-of-function KCNQ2/3 mutations, will provide new insight into cortical physiology in health and disease. To this end, we will: (i) determine the function of KCNQ2/3 channels in immature PV+ and SST+ interneurons using cell-type specific genetics, (ii) determine whether loss of KCNQ2/3 activity from PV+/SST+ interneurons translates to changes in their population rhythmic activity ex vivo and in vivo using novel imaging approaches and (iii) determine whether gain-of- function KCNQ2/3 mutations lead to interneuron hypoexcitability. The proposed research will make a significant contribution to our broader understanding of how KCNQ2/3 channels control neuronal excitability, building a foundation for the prevention and treatment of neurological disorders such as pediatric epilepsy.