Abstracts

Rationale: 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. During this period, a number of cellular alterations occur in the hippocampus including increased proliferation of neural progenitors, production of ectopic granule cells (EGCs), mossy fiber sprouting (MFS), neuronal hypertrophy and persistence of hilar basal dendrites. 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. Methods: In this study,  Nestin-δ-HSV-thymidine kinase transgenic mice [Nestin-TK] was used to specifically ablate newborn neurons in adult mice using Ganciclovir (GCV) at different time points after acute seizures.  Video-EEG monitoring was performed to measure SRS and immunohistochemistry was done to specifically assess the number of EGCs and MFS in both ablated and non-ablated (control) group of animals in correlation with reduced SRS. Results: Using the methods described above, we show that there is a 65% reduction in SRS with chronic ablation of aberrant neurogenesis for 2 months with a significant reduction in EGCs.  Conclusions: Based on our results, we conclude that there is a critical window in the period of epileptogenesis where optimal ablation of aberrant neurogenesis after acute seizures can suppress the development of chronic seizures. We provide evidence that ablation of neurogenesis after the brain insult can lead to a significant reduction in SRS. These data suggest there may be a therapeutic window to block aberrant neurogenesis after epilepsy has already developed and this finding is highly signifciant and of interest to basic resarchers and clinicians.  Funding: We are grateful for our funding from NIH for this work