Repetitive Spreading Depolarization induces the activation of cell differentiation, synaptic plasticity and neuroprotective pathways.

Spreading depolarization (SD) is a slowly propagating wave of profound depolarization that sweeps through cortical tissue. While much emphasis has been placed on the damaging consequences of SD, it is possible that SDs also activate compensatory pathways related to cell survival and plasticity. The present study aimed to provide an unbiased assessment of gene expression changes following SD, as well as novel molecular networks associated with these transcriptional alterations. SD clusters were induced with either focal application of KCl or with optogenetic stimulation in healthy mice, and then 2 hours later cortical RNA was extracted and sequenced. SD's significantly increased the expression of 21 genes - no genes were significantly downregulated. Notable top hits included the immediate early genes FOS, ARC, and JUN, the cell proliferation-related gene DUSP6, the plasticity-related gene HOMER1, and inflammation related genes PTGS2, EGR2, and NR4A1. Pathway analysis identified the recruitment of genes associated with axonogenesis, branching, neuritogenesis, and dendritic growth, as well as inhibition of pathways associated with cell death, apoptosis, and neuronal degeneration. These results identify the induction of plasticity and/or circuit modification as an important consequence of SDs in healthy tissue, as well as specific gene targets and pathways amenable to manipulation in follow up studies.