Project Summary Neuroinflammation has been identified as a therapeutic target for acquired epilepsy. However, if and how mitochondria contribute to neuroinflammatory processes such as astrogliosis remains unknown. The goal of this proposal is to determine if mitochondrial reactive oxygen species (mtROS) generated within neurons can activate astrogliosis. This non-cell autonomous regulation is hypothesized to occur by posttranslational redox modification of glial fibrillary acidic protein (GFAP) resulting in long-lasting neuroinflammation and epilepsy. To test this idea, we plan to utilize a combination of tools and approaches including embryonic and inducible mouse models lacking mitochondrial superoxide dismutase in forebrain neurons, 2-photon imaging of astrocytic calcium, mitochondria-specific models, and mass spectrometry. The following specific aims will be explored. Specific Aim 1: Determine if mitochondrial oxidative stress is sufficient to increase astrogliosis in vitro. Specific Aim 2: Determine the role of neuronal mtROS in GFAP upregulation and astrogliosis in vivo. Specific Aim 3. Determine the role of mtROS in GFAP upregulation, astrogliosis, epilepsy and/or cognitive dysfunction in chemoconvulsant epilepsy models. Potential clinical application of the proposal includes identification of novel metabolism-based therapies to target astrogliosis in epilepsy.