Aberrant hippocampal neurogenesis produces glial cells in epilepsy: new targets for regenerative medicine

JOURNAL/rmrep/04.03/02273995-202503000-00002/figure1/v/2025-03-10T115452Z/r/image-tiff Epilepsy is often seen to present with perturbations to adult hippocampal neurogenesis, a process intrinsically linked with neuro-regeneration and plasticity in the brain. As adult-born neurons are exceptionally rare within the nervous system, adult hippocampal neurogenesis is an attractive target for regenerative medicine. The increased neuronal activity in the epileptic brain leads to increased production of newborn cells and altered integration of new neurons within the hippocampus. Glial cells are important contributors to the neurogenic niche and astrocytes also exhibit a specific pathological response in the hippocampus of temporal lobe epilepsy patients. Here, we set out to investigate the increased number of astrocytes following status epilepticus and their association with adult hippocampal neurogenesis. Initial investigations employed immunolabeling of brain sections from the mouse intra-amygdala kainic acid model of epilepsy and were corroborated with publicly available single-cell RNA sequencing datasets of human tissue to assess newborn cells in the dentate gyrus. We found an increased number of immature neurons and reactive astrocytes in the epileptic mouse hippocampus. Additionally, we identified a cell population that expressed both neurogenesis (doublecortin) and astrocyte (glial fibrillary acidic protein) markers in the epileptic brain of both mice and humans. We further evaluated the expression profile of this cell population. Immunolabeling of mouse tissue showed that cells expressing both, doublecortin and glial fibrillary acidic protein, also expressed mature astrocyte markers aquaporin 4 and glutamate transporter-1. Human single-cell RNA sequencing data highlighted the expression of neurogenesis and astrocyte markers in the doublecortin/glial fibrillary acidic protein-expressing cells. These findings suggest chronic epilepsy may drive early neuroblasts to fate-switch to an astrocyte lineage. Further studies may reveal the mechanisms that promote neuroblast fate-switching and whether this can or should be prevented, thereby providing new targets for regenerative medicine in epilepsy and perhaps other neurologic diseases.