CFTR Modulates Hypothalamic Neuron Excitability to Maintain Female Cycle.

Cystic fibrosis transmembrane conductance regulator (CFTR), known as an epithelial Cl channel, is increasingly noted to be expressed in the nervous system, although whether and how it plays a role in neuronal excitability is unclear. Given the association of CFTR with fertility, we tested here possible involvement of CFTR in regulating hypothalamic neuron excitability. Patch-clamp and Ca imaging showed that pharmacological inhibition of CFTR evoked electrical pulses and Ca spikes in primary rat hypothalamic neurons, which was dependent on extracellular Cl. 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 eliminated hypothalamic electrical pulses in the wild-type brain slices, which was reversible by subsequent addition of Cl. In adult female mice, Ca indicator (GCaMP6s)-based fiber-photometry showed that hypothalamic Ca 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.