NG2 glia-derived GABA release tunes inhibitory synapses and contributes to anxiety-like behavior in chronic social defeat stress

NG2 glia, also known as oligodendrocyte precursor cells (OPCs), play an important role in proliferation and give rise to myelinating oligodendrocytes during early brain development. In contrast to other glial cell types, the most intriguing aspect of NG2 glia is their ability to directly sense synaptic inputs from neurons. However, whether this synaptic interaction is bidirectional or unidirectional, or its physiological relevance has not yet been clarified. Here, we report that NG2 glia form synaptic complexes with hippocampal interneurons and that selective photostimulation of NG2 glia (expressing channelrhodopsin-2) functionally drives GABA release and enhances inhibitory synaptic transmission onto proximal interneurons in a microcircuit. The mechanism involves GAD67 biosynthesis and VAMP-2 containing vesicular exocytosis. Further, behavioral assays demonstrate that NG2 glia photoactivation triggers an anxiety-like behavior in vivo and induces anxiety-like behavior in a mouse model of chronic social defeat stress. Overall design: Single-cell RNA seq of sorted NG2 glial cells of 3-week-old Pdgfra-creERTM; Rosa26-mGFP mouse