Neuronal circuitry mechanism regulating adult quiescent neural stem cell fate decision

Abstract

Adult neurogenesis arises from neural stem cells within specialized niches ^{1– 3} . Neuronal activity and experience, presumably acting upon this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival ^{1, 3} . Whether local neuronal circuitry has a direct impact on adult neural stem cells is unknown. Here we show that in the adult hippocampus nestin-expressing radial glia-like quiescent neural stem cells ^{4– 9} (RGLs) respond tonically to the neurotransmitter GABA via γ ₂ subunit-containing GABA _A Rs. Clonal analysis ⁹ of individual RGLs revealed a rapid exit from quiescence and enhanced symmetric self-renewal after conditional γ ₂ deletion. RGLs are in close proximity to GAD67 ⁺ terminals of parvalbumin-expressing (PV ⁺) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of dentate PV ⁺, but not somatostatin- or vasoactive intestinal polypeptide (VIP)-expressing, interneuron activity can dictate the RGL choice between quiescence and activation. Furthermore, PV ⁺ interneuron activation restores RGL quiescence following social isolation, an experience that induces RGL activation and symmetric division ⁸ . Our study identifies a niche cell-signal-receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.