FosB is part of a homeostatic mechanism that protects the epileptic brain from further deterioration

Activity induced transcription factor Delta FosB plays a key role in different CNS disorders including epilepsy, Alzheimer's disease, and addiction. Recent findings suggest that Delta FosB drives cognitive deficits in epilepsy and together with the emergence of small molecule inhibitors of Delta FosB activity makes it an interesting therapeutic target. However, whether Delta FosB contributes to pathophysiology or provides protection in drug-resistant epilepsy is still unclear. In this study, Delta FosB was specifically downregulated by delivering AAV-shRNA into the hippocampus of chronically epileptic mice using the drug-resistant pilocarpine model of mesial temporal epilepsy (mTLE). Immunohistochemistry analyses showed that prolonged downregulation of Delta FosB led to exacerbation of neuroinflammatory markers of astrogliosis and microgliosis, loss of mossy fibers, and hippocampal granule cell dispersion. Furthermore, prolonged inhibition of Delta FosB using a Delta JunD construct to block Delta FosB signaling in a mouse model of Alzheimer's disease, that exhibits spontaneous recurrent seizures, led to similar findings, with increased neuroinflammation and decreased NPY expression in mossy fibers. Together, these data suggest that seizure-induced Delta FosB, regardless of seizure-etiology, is part of a homeostatic mechanism that protects the epileptic brain from further deterioration.