KCNQ2/3 channels and interneuron physiology

点击翻译按钮获取中文摘要

KCNQ2/3 channels have emerged as essential regulators of neonatal brain excitability, highlighted by the several loss- and gain-of-function KCNQ2 and KCNQ3 variants that 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 developing new therapeutics for neonatal epilepsy. Over the last several years, 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. Here we propose experiments to tackle important outstanding questions regarding the function and properties of KCNQ2/3 potassium channels in interneurons. Interneurons are critical for shaping the activity of neuronal populations and promoting the development of excitatory synaptic circuits. KCNQ2/3 channels are expressed early in development when interneurons have not yet fully developed their clade of unique potassium channels, raising the possibility that KCNQ2/3 channels might control interneuron properties at early developmental stages. One explanation is that a decrease in interneuron excitability leads to the hyperexcitability phenotype of the gain-of-function KCNQ2/3 variants in epileptic encephalopathy. Thus, elucidating the role of KCNQ2/3 channels in interneuron excitability and exploring the effects of known gain-of-function KCNQ2/3 variants will shed new insights into cortical physiology in health and disease. To this end, we will: (i) determine the function of KCNQ2/3 channels in immature parvalbumin (PV)- and somatostatin (SST)-positive interneurons using cell-type specific genetics, (ii) determine whether Kcnq2/3 ablation from interneurons leads to network excitability ex vivo and in vivo, and (iii) determine whether gain-of-function KCNQ2/3 variants lead to interneuron hypoexcitability and subsequent excitatory network hyperexcitability. The proposed research will significantly contribute 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.