Genetic and Stress-Induced Loss of NG2 Glia Triggers Emergence of Depressive-like Behaviors through Reduced Secretion of FGF2

NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders. •NG2 glia loss affects the glutaminergic systems in the PFC•NG2 glia loss in the PFC induces behavioral deficits via loss of secreted FGF2•NG2 glia density is reduced in subjects with MDD and in susceptible mice after SDSP•Restoration of NG2 glia density rescues cellular and behavioral aberrations Functional contribution of glia to the pathophysiology of mental disorders is poorly understood. Birey and colleagues describe a role for NG2 glial cell in mediating CNS homeostasis, the loss of which leads to the emergence of depressive-like behaviors in mice.