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

Abstract

SUMMARY 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.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…NG2+ glia cells connect with axons using primitive glutamatergic synapses and probably direct the formation of both glutamatergic and GABAergic synapses during the brain development before myelination (Dimou and Gallo, 2015). Exposure to preclinical stress paradigms led to decreases in number and density of NG2+ cells among lab animals (Birey et al, 2015) and loss of NG2+ was associated with decreased astrocytic EAATs activity and glutamate increases in prefrontal and hippocampal regions (Banasr et al, 2010;Birey et al, 2015). The depression-like symptoms associated with NG2+ loss responded to antidepressant medications and electroconvulsive treatments, both of which are known to alter glutamatergic neurotransmission in addition to other neurotransmitters (Banasr and Duman, 2008;Banasr et al, 2007;Sanacora and Banasr, 2013).…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…No changes were observed in the dorsal striatum, while different electrophysiological phenotypes have been found in the somatosensory cortex (where both mEPSC frequency and decay were increased), indicating a differential contribution of NG2 glia in the regulation of glutamatergic neurotransmission in distinct brain regions. By using this ablation strategy, NG2 glia loss did not result in brain vasculature alterations, inflammation, microglia activation, or neurodegeneration [87].…”

“…Reduced levels of the immunomodulatory factor hepatocyte growth factor (HGF) have been proposed to mediate such effects. The different outcomes of NG2 glia ablation in the two studies may be interpreted again as the result of the loss of region-specific functions exerted by NG2 glia, or may be related to the different extent and timing of cell ablation (about 50% of NG2 glia in the cortex after seven days in [87]; about 80% in the hippocampus after one day in [88]). Milder effects reported in Birey et al [87] may be indicative of the persistence of a sufficient number of NG2 glia contributing to neuronal support in the mouse cortex.…”

“…By using a transgenic mouse model expressing the diphtheria toxin receptor (DTR) under the control of the NG2 promoter (NG2Cre-R26DTR mice), Birey and colleagues [87] showed that the selective ablation of about 50% of NG2 glia in adult mice caused deficits in the glutamatergic neurotransmission (i.e., decreased amplitude and increased decay of the miniature excitatory postsynaptic currents (mEPSC), and an altered postsynaptic glutamate receptor trafficking in pyramidal excitatory neurons), negatively affected the astrocytic extracellular glutamate uptake, and induced depressive-like behaviors in mice. Of note, these effects could be observed only in the prefrontal cortex.…”

Altered Microbiota Composition Mediates Depressive Behavior During Chronic Stress

“…Recently, loss of oligodendrocyte progenitor cells (OPCs) was shown to initiate depressive behavior in animal models 225 . This subset of glial cells, precursors to myelinating oligodendrocytes, fluctuates in number during demyelinating inflammation, particularly at lesion sites 226,227 .…”