Chronic ablation of aberrant hippocampal neurogenesis to prevent epilepsy

Mesial temporal lobe epilepsy (mTLE) is the most common form of adult acquired epilepsy. Unfortunately, it is frequently resistant to current anti-epileptic drugs and often times surgical therapy is the best available option for these individuals. While genetic mutations and developmental malformations can cause mTLE, it is usually caused by a brain injury such as head trauma, infection, ischemia, prolonged febrile seizures and status epilepticus. Moreover, acute seizures triggered by an initial brain insult is usually followed by a “latent period” before clinically detectable seizures appear eventually culminating in spontaneous recurrent seizures (SRS). The existence of this latent period is also called the period of “epileptogenesis” which provides a hopeful window for therapeutic intervention where development of epilepsy can be prevented in the susceptible individual. It has been shown that ablation of newborn neurons prior to the brain insult reduces the frequency of SRS by 40% along with a significant reduction in EGCs with no change in MFS. While other studies have used similar approaches to target various populations of newborn neurons to prevent epilepsy, it still remains an open question whether targeting aberrant neurogenesis in a realistic therapeutic window after the brain insult will reduce SRS. In this study, using Nestin-d-HSV-thymidine kinase transgenic mice [Nestin-TK] to specifically ablate newborn neurons in adult mice at different time points after acute seizures and video-EEG monitoring to measure SRS, we show that there is a 65% reduction in SRS with 8 weeks and not 4 weeks of ablation of aberrant neurogenesis specifically after acute seizures with a significant reduction in aberrant histopathology. Thus this study opens up ways for understanding the critical epileptogenic window where assessing the cellular changes responsible for reduction in chronic SRS can help in developing interventions for the prevention of epilepsy.