Early life adversity targets the transcriptional signature of hippocampal NG2+ glia and affects voltage gated sodium (Na _v) channels properties

Abstract

The precise mechanisms underlying the detrimental effects of early life adversity (ELA) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELA, in the form of a limited bedding and nesting material (LBN) paradigm, on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. First, we have established a link between maternal behavior, activation of the offspring's stress response and heterogeneity in the outcome to LBN manipulation. We further showed that LBN targets the hippocampal NG2+ transcriptome with glucocorticoids being an important mediator of the LBN-induced molecular changes. LBN altered the NG2+ transcriptome and these transcriptional effects were correlated with glucocorticoids levels. The functional relevance of one LBN-induced candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Na _v) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in LBN animals, which displayed impaired cognitive performance. Considering that Na _v channels are important for NG2+ cell-to-neuron communication, our findings provide novel insights into the disruption of this process in LBN mice.