Cystic fibrosis transmembrane conductance regulator (CFTR) downregulates the excitability of deep pyramidal neurons in the rodent cortex

The cystic fibrosis transmembrane conductance regulator (CFTR) is an ATP-binding chloride channel that is regulated by intracellular cAMP/PKA phosphorylation. CFTR is widely expressed in peripheral tissues and organs of mammals and plays a vital role in maintaining chloride balance and cellular homeostasis. While preliminary studies have identified CFTR expression in the central nervous system (CNS), it is not clear whether this channel also modulates the neural network of the cerebral cortex by regulating the intracellular chloride level of neurons. In this study, we employed immunohistochemical staining, patch-clamp recording, and two-photon imaging techniques to comprehensively analyze the functions of the CFTR channel in the rodent cortex. Our results indicate that CFTR is primarily distributed in the deep pyramidal somata and superficial axons of the cerebral cortex. Regulation of CFTR has the potential to alter the resting membrane potential and evoke action potentials of layer V pyramidal neurons, which produces significant changes in inhibitory synaptic transmission. Furthermore, we found that inhibiting CFTR channels increased the calcium activity of axon boutons and somata of the primary motor cortex in vivo, promoting motor learning. Overall, these findings implicate a crucial role of CFTR in modulating Cl-homeostasis and neuronal excitability in the cerebral cortex, furthering our understanding of the functions of the chloride channel in the central nervous system.