Neuron-specific Mitochondrial Oxidative Stress Results in Epilepsy, Glucose Dysregulation and a Striking Astrocyte Response

September 15, 2021

Featuring the work of CURE Epilepsy Advisor and grantee Dr. Manisha Patel

Abstract, originally published in Neurobiology of Disease

Mitochondrial superoxide  (O2radical dot) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal  O2radical dot 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  O2radical dot 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.