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Given the association of CFTR with fertility, we tested here possible involvement of CFTR in regulating hypothalamic neuron excitability. Patch-clamp and Ca2+ imaging showed that pharmacological inhibition of CFTR evoked electrical pulses and Ca2+ spikes in primary rat hypothalamic neurons, which was dependent on extracellular Cl\u2212. Hypothalamic neurons in brain-slice preparations from adult female mice with CFTR mutation (DF508) exhibited significantly reduced electrical pulses as compared to the wild-type controls. Removal of extracellular Cl\u2212 eliminated hypothalamic electrical pulses in the wild-type brain slices, which was reversible by subsequent addition of Cl\u2212. In adult female mice, Ca2+ indicator (GCaMP6s)-based fiber-photometry showed that hypothalamic Ca2+ activities in vivo were enhanced at the proestrus\/estrus phase as compared to the diestrus phase of the female cycle. Such estrus-associated hypothalamic activities were largely diminished in DF508 female mice, together with delayed puberty and disturbed female cycles. Therefore, these findings suggest a critical role of CFTR in modulating hypothalamic neuron excitability, which may account for the disturbed female cycles and reduced female fertility associated with CFTR mutations.<\/jats:p>","DOI":"10.3390\/ijms241612572","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:26:39Z","timestamp":1691497599000},"page":"12572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["CFTR Modulates Hypothalamic Neuron Excitability to Maintain Female Cycle"],"prefix":"10.3390","volume":"24","author":[{"given":"Yong","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China"},{"name":"Department of Physiology, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3657-5477","authenticated-orcid":false,"given":"Yanting","family":"Que","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China"},{"name":"Department of Physiology, Jinan University, Guangzhou 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China"},{"name":"Department of Physiology, Jinan University, Guangzhou 510632, China"},{"name":"School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4266-6789","authenticated-orcid":false,"given":"Ye Chun","family":"Ruan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11811","DOI":"10.1074\/jbc.274.17.11811","article-title":"The cystic fibrosis transmembrane conductance regulator activates aquaporin 3 in airway epithelial cells","volume":"274","author":"Schreiber","year":"1999","journal-title":"J. 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