CELLULAR PHYSIOLOGY OF EPILEPSY-ASSOCIATED KCNQ2 and KCNQ3 CHANNELS

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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.