Neuronal circuitry mechanism regulating adult quiescent neural stem cell fate decision

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.