Early life stress programming of NG2+ glia transcriptome alters functional properties of voltage gated sodium (Nav) channels and cognitive performance

Abstract

Background: The detrimental effects of early adversity on brain development and adult mental health are well established. While studies have identified myelination processes and oligodendrocytes as targets of early adversity across species, knowledge about the precise molecular mechanisms and cell populations involved is still lacking. NG2+ cells are oligodendrocyte precursor cells with unique properties, as they form synapses with neurons, engage in cell-cell communication and respond to stress hormones. Methods: Using an established mouse model of early life stress (ELS) we performed cell-type specific molecular profiling in hippocampal NG2 cells at early postnatal and adult stages. To further dissect the impact of glucocorticoids on ELS-induced transcriptional changes, we integrated our data with available Chip-seq data on genomic binding sites of the glucocorticoid receptor (GR). The functional relevance of one candidate gene, Scn7a, was confirmed by electrophysiological recordings in hippocampal NG2 cells. Results: ELS specifically targeted the hippocampal NG2 cell transcriptome, and the molecular changes correlated with the ELS-induced increase of corticosterone. The overlap analysis with Chip-seq data on genomic binding sites of the GR revealed nine overlapping genes. Among those Scn7a, coding for a subunit of sodium channels, remained upregulated until adulthood in ELS animals. Upregulation of Scn7a was accompanied by an increase in the density of voltage-gated sodium channel activated currents in hippocampal NG2 cells. Conclusions: Our findings indicate that ELS specifically targets the transcriptional profiles and electrophysiological properties of hippocampal NG2 glia. Considering that voltage-gated sodium channels are important for the NG2 cell-to-neuron communication, our findings may provide novel insights into the pathophysiological processes underlying stress related mental disorders.