Publication Date
10-1-2021
Journal
Neurobiology of Disease
DOI
10.1016/j.nbd.2021.105470
PMID
34371143
PMCID
PMC8939287
PubMedCentral® Posted Date
10-1-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Astrocytes, Behavior, Animal, Electroencephalography, Epilepsy, Glial Fibrillary Acidic Protein, Glucose Metabolism Disorders, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Motor Activity, Neurons, Oxidative Stress, Primary Cell Culture, Rats, Superoxide Dismutase, Superoxides
Abstract
Mitochondrial superoxide (O2.−) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2.− to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2-3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2.−, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2.− is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.
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Cell and Developmental Biology Commons, Genetics and Genomics Commons, Immunology and Infectious Disease Commons, Medicine and Health Sciences Commons, Microbiology Commons, Molecular Biology Commons, Neuroscience and Neurobiology Commons
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