Saturday, May 17, 2025
5/17/2025
Glial KCNQ channels. - Project Summary/Abstract KCNQ channels are members of a conserved family of voltage-gated potassium channels. KCNQ2 through KCNQ5 subunits are expressed in the nervous system, where they regulate neuronal excitability. Epilepsy, autism, and other neurological conditions have been associated with mutations in the KCNQ channel genes expressed in the nervous system. Although evidence supports the expression of KCNQ channels both in neurons and in glia, the role of these channels in glial cells is still unknown. In this study, we use C. elegans to investigate the physiological function of KCNQ channels in glia and the consequences of glial KCNQ pathogenic mutations. Using RNA sequencing we have found that the amphid glia, a pair of glial cells that encapsulate sensory neurons in the amphid sensory organ, express KCNQ worm homolog kqt- 2. Preliminary behavioral and Ca2+ imaging experiments suggest reduced GABA release from glia of kqt-2 knockout and glial knock down worms. Importantly, expression in amphid glia of human KCNQ2 and KCNQ3 genes rescue the kqt-2 knockout phenotype, supporting conservation of function across species. Thus, our preliminary results suggest that glial KCNQ channels may be needed in glia to dampen neuronal activity via GABA release. In this application we will test this hypothesis through the following 3 specific aims: 1) To establish to what extent the function of glia and neurons is altered in kqt-2 knockout; 2) To determine the physiological properties of KCNQ channels in glia; and 3) To establish the consequences of glial KCNQ pathogenic mutations on glial and neuronal structure and function. Our findings suggest a paradigm shift: neuronal output is regulated not only by neuronal KCNQ channels but also by glial KCNQs. Our work will shed light on the underlying mechanism of this regulation and will determine the contribution of pathogenic glial KCNQ mutation to the expression of the phenotype.
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