GABAergic precursors grafts in animal models of epilepsy

Abstract

Introduction: Refractory epilepsy is present in about 30% of TLE patients, despite carefully optimized drug treatment. These patients have no treatment other than major resective surgery. In the last years, cell-based therapies have emerged as a promising alternative. Recently, we have demonstrated that MGE-derived precursors transplanted into the normal adult and neonatal telencephalon migrate, differentiate and incorporate as fully functional GABAergic interneurons. Moreover, grafting in a mouse model of hyperactivity, generated by partial elimination of GABAergic interneurons, replaced the deficit in interneurons and restored the normal levels of inhibition in the ablated hippocampus. To further analyze the use of these precursors as an antiepileptic therapy for refractory TLE epilepsy, we have performed transplants in the pilocarpine mouse model of epilepsy. Results: Intrahippocampal bilateral transplants of GFP+ cells from the MGE were performed 5 days after pilocarpine induction of status epilepticus. We monitorized the control and transplanted mice daily from 2 weeks to 4 months after the transplant to asses the possible antiepileptic effects. We observed a significant delay in the latency time to develop the spontaneous recurrent seizures (SRS) in the transplanted group. In addition, the percentage of transplanted mice that fully developed the SRS was significantly reduced with respect their controls and this small group suffered the SRS four times less frequently. Immohistochemical analysis reveled that GFP+ cells spread widely through CA and DG areas. They differentiated into normal interneuron subtypes, with mature morphology and expressing specific markers such as parvalbumin, somatostatin, NP-Y, and calretinin. Interestingly, we observed a protective effect on the hippocampal sclerosis, correlated with reduced levels of cell death. Grafted cells did not affect the sprouting of mossy fibers, although we cannot discard a direct interaction with the grafted cells. In fact, patch clamp analysis of sIPSC in the grafted area confirmed a modulation of the inhibitory synaptic function. Conclusion: MGE-derived precursor grafts into the hippocampus protects against the development of TLE and elicit a reduction in hippocampal sclerosis. This cell-based therapy could be extremely beneficial for the treatment of refractory epilepsy.