The Neurotransmitter VIP Expands the Pool of Symmetrically Dividing Postnatal Dentate Gyrus Precursors via VPAC2 Receptors or Directs Them Toward a Neuronal Fate via VPAC1 receptors

The controlled production of neurons in the postnatal dentate gyrus and thoughout life is important for hippocampal learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation‐neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Here we show that vasoactive intestinal polypeptide, a neuropeptide coreleased with GABA under specific firing conditions, is uniquely trophic for proliferating postnatal nestin‐positive dentate NSPCs, mediated via the VPAC2 receptor. We also show that VPAC2 receptor activation shifts the fate of symmetrically dividing NSPCs toward a nestin‐only phenotype, independent of the trophic effect. In contrast, selective VPAC1 receptor activation shifts NSPC fate toward granule cell neurogenesis without any trophism. We confirm a trophic role for VPAC2 receptors in vivo, showing reduced progeny survival and dentate neurogenesis in adult Vipr2−/− mice. We also show a specific reduction in type 2 nestin‐positive precursors in vivo, consistent with a role for VPAC2 in maintaining this cell population. This work provides the first evidence of differential fate modulation of neurogenesis by neurotransmitter receptor subtypes and extends the fate‐determining effects of neurotransmitters to maintaining the nestin‐positive pool of NSPCs. This differential receptor effect may support the independent pharmacological manipulation of precursor pool expansion and neurogenic instruction for therapeutic application in the treatment of cognitive deficits associated with a decline in neurogenesis. STEM CELLS 2009;27:2539–2551