Astrocyte-derived PEA116 increases adult hippocampal neurogenesis and confers stress resilience

In the dentate gyrus of the hippocampus, the neurogenic niche regulates several steps of adult neurogenesis, from the proliferation to the integration of newly formed neurons in the hippocampal network. However, the role of astrocytes in the regulation of adult neural stem cell (aNSC) proliferation is still little described. Here, we found that blocking vesicular release from astrocytes decreased cell proliferation in the dentate gyrus, resulting in impaired adult neurogenesis. Inversely, astrocyte-conditioned medium increased cell proliferation in a vesicular release-dependent manner. We identified PEA116 as a peptide released by astrocytes, that is derived from the c-terminal portion of the PEA15 protein and increased cell proliferation. PEA116 increased ERK2 phosphorylation, decreased the expression of genes involved in aNSC quiescence, resulting in aNSC quiescence exit. The ensuing increase in hippocampal neurogenesis improved resilience to chronic stress. These findings highlight a novel peptide produced by astrocytes that regulates the early steps of adult neurogenesis, with an implication for mood disorders.