Role of cyclic nucleotide-gated channels in the modulation of mouse hippocampal neurogenesis

Neural stem cells generate neurons in the hippocampal dentate gyrus in mammals, including humans, throughoutadulthood. Adult hippocampal neurogenesis has been the focus of many studies due to its relevance in processessuch as learning and memory and its documented impairment in some neurodegenerative diseases. However, weare still far from having a complete picture of the mechanism regulating this process. Our study focused on thepossible role of cyclic nucleotide-gated (CNG) channels. These voltage-independent channels activated by cyclicnucleotides, first described in retinal and olfactory receptors, have been receiving increasing attention for theirinvolvement in several brain functions. Here we show that the rod-type, CNGA1, and olfactory-type, CNGA2,subunits are expressed in hippocampal neural stem cells in culture and in situ in the hippocampal neurogenic nicheof adult mice. Pharmacological blockade of CNG channels did not affect cultured neural stem cell proliferation butreduced their differentiation towards the neuronal phenotype. The membrane permeant cGMP analogue, 8-Br-cGMP,enhanced neural stem cell differentiation to neurons and this effect was prevented by CNG channel blockade. Inaddition, patch-clamp recording from neuron-like differentiating neural stem cells revealed cGMP-activated currentsattributable to ion flow through CNG channels. The current work provides novel insights into the role of CNGchannels in promoting hippocampal neurogenesis, which may prove to be relevant for stem cell-based treatment ofcognitive impairment and brain damage.