Neuropeptides modulate local astrocytes to regulate adult hippocampal neural stem cells and neurogenesis

It has been well established that parvulbumin (PV) interneurons in the adult dentate gyrus (DG) regulate radial-glia like neural stem cells (rNSCs) through tonic GABA signaling. However, several major local interneuron subtypes co-release GABA and neuropeptides. Virtually nothing is known about whether and how endogenous neuropeptides regulate rNSCs. Here we demonstrate an unprecedented role of endogenous CCK in regulating rNSCs and hippocampal neurogenesis through distinctive states of the local astrocytes. Specifically, stimulating CCK release leads to increased Ca2+ transients in local astrocytes, and the subsequent astrocytic glutamate release promotes rNSC proliferation and neurogenesis via glutamate receptor mediated MAPK/ERK signaling cascade. In contrast, suppression of CCK synthesis switches resident astrocytes to a reactive state, which leads to decreased proliferation of rNSCs by regulating a gene network that negatively regulates rNSC proliferation. These findings have broad implications in multiple neuropathological conditions associated with altered CCK level, neuroinflammation, and impaired hippocampal neurogenesis. Gene expression analyses were performed on mRNA samples isolated from the dentate gyrus (right side) of adult mice treated with shScrambled or shCCK.