Regulation of neurogenesis and neuronal migration by Rrm2 and Timp3 following seizures.

Abstract

Temporal lobe epilepsy is associated with aberrant neurogenesis and ectopic migration of adult-born granule cells (abGCs), yet the molecular mechanisms driving these changes remain poorly defined. Using a pilocarpine-induced mouse model of temporal lobe epilepsy and chemogenetic silencing of abGCs via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we previously demonstrated that abGC inhibition reduces both ectopic migration and seizure susceptibility. To identify underlying molecular regulators, we performed RNA sequencing of FACS-isolated abGCs and identified Rrm2 and Timp3 as top candidate genes modulated by seizure activity and neuronal silencing. To assess their functional roles, we pharmacologically inhibited Rrm2 with Triapine (3-AP) and Timp3 with the LXR agonist T0901317 (T09). Inhibition of Rrm2 significantly reduced seizure frequency, decreased hilar abGC migration, and altered the proportion of immature neurons arising from dividing progenitors. While T09 treatment did not significantly alter Timp3 transcript levels, it increased the number of DCX+ neurons in the hilus without affecting seizure burden, suggesting an effect on neuronal migration independent of robust Timp3 knockdown. These findings highlight distinct roles of Rrm2 and Timp3 in hippocampal plasticity following seizures. Together, these data identify new molecular targets for modulating aberrant neurogenesis in epilepsy.