This study identified gene expression changes after repeated spreading depolarizations (SD) in healthy and injured brains. A large range of expression changes implicate SD in both deleterious and protective/adaptive changes. SDs are typically assumed to be purely damaging events, and thus increases seen in pathways related to neuronal growth and regeneration were surprising. Further studies of mechanisms underlying possible protective effects of SD could lead to new approaches to improve outcomes following stroke and trauma.
Spreading depolarization (SD) is a slowly propagating wave of profound depolarization that sweeps through cortical tissue. SD is not harmful to healthy brain tissue, but can cause irrecoverable injury to metabolically compromised tissue, and thus, causes expansion of acute brain injuries. SDs occur in stroke brain, usually originating near ischemic foci and propagating relatively widely throughout peri-infarct and surrounding tissue leading to tissue loss. Despite clear deleterious consequences, previous studies have shown changes in expression levels of genes known to regulate synaptic plasticity and neurogenesis following SD. The present study aimed to perform an extensive, unbiased analysis to identify a more complete range of biological pathways modified by SD.
SDs were induced repetitively (4 SDs at 30 min intervals) in both healthy mice or in a model of stroke (dMCAO). Two hours after onset of the initial SD, cortical slices were collected and/or total RNA was extracted.
RNA-seq and spatial genomics identified differentially expressed genes (DEGs). Consistent with previous studies, top DEGs include genes encoding the neurotrophic factor BDNF and VGF, as well as intermediate early genes ARC, FOS, JUN and EGR. Among other DEGs with significantly increased levels include HOMER1, COX2, ADRB1, NR4A1, COX2, DUSP6, and KCNJ2. Pathway analysis revealed significant increases in the expression of genes associated with axogenesis, branching of axons, neuritogenesis, dendritic growth, and regeneration of neurites. We also found a significant decrease in expression in genes associated with cell death, apoptosis and neuronal degeneration. Notably, how these pathways are predicted to be activated or inhibited also differs between: infarct core, distal, and contralateral areas. These results identified a range of novel targets that could be used to test whether clusters of SD may enhance plasticity or recovery in surviving peri-infarct tissue, in addition to the well-established role of SD in expansion of infarct core.
Dell'Orco, Michela; Lu Li; Jordan Weisend; Nora I. Perrone-Bizzozero; Lee Anna Cunningham; Russel Morton; Andrew P. Carlson; and William Shuttleworth. "Identification of neuronal injury and survival mRNA pathways after spreading depolarization." (2022). https://digitalrepository.unm.edu/hsc-bbhrd/35