Zwagerman, Nathan T.; Richardson, R. Mark
Mesial temporal lobe epilepsy (MTLE) is the most common form of adult epilepsy and is characterized by pathophysiology in the mesial temporal structures. It has been associated with a 30 to 40% rate of pharmacoresistance, and surgical resection offers the only potential for cure. A proposed mechanism for seizure generation in these patients is loss of inhibitory interneurons leading to hypersynchrony of principle cell firing, ultimately culminating in seizure generation and propagation. Cell transplantation of inhibitory interneurons into the mesial temporal lobe to replace inhibitory control is a proposed strategy for the surgical treatment of epilepsy that if successful would offer some advantages over emerging techniques that require implanted devices, like brain stimulation. Enhancement of GABA-mediated synaptic inhibition previously was correlated with the transplantation of medial ganglionic eminence (MGE)-derived interneurons to the healthy adult mouse hippocampus. Baraban and colleagues (GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci. 2013 Jun) have now reported a thorough characterization of the transplantation of MGE cells into an adult mouse epilepsy model.
In their recent report, the group harvested cells from the mouse fetal MGE and transplanted the cells into the hippocampus or amygdala of pilocarpine-treated adult mice that had demonstrated at least one seizure on video-EEG. The mice were then observed and compared to non-pilocarpine treated controls as well as to epileptic mice that received vehicle-only injections. The authors provided neurochemical and electrophysiological evidence that about 63% of transplanted MGE cells become functional interneurons. At 60 days after treatment, mice were assessed for seizure frequency and those receiving hippocampal transplants demonstrated a 92% reduction in seizure frequency with 50% having no seizures during the 7 to 10 day observation period (Figure 1). There was no anti-seizure effect observed following transplantation to the amygdala, although it should be noted that four times less cells were transplanted there. To shed light on the possibility that restoration of inhibitory control could improve neurobehavioral side effects of pilocarpine that may be relevant to similar comorbidities in human epilepsy, the authors performed several behavioral tests. These results were variable, with hippocampal transplantation appearing to improve spatial learning and aggressive behavior but not measures of despair and anxiety.
This study is not the first to report the efficacy of neural progenitor cell transplantation in a rodent epilepsy model, but it is by far the most comprehensive. Some limitations need to be taken into account, such as the lack of a live cell control. While this cell transplantation strategy avoids the need for chronic device implantation, practical limitations still include cell survival (15%), the fetal source, and the requirement for multiple injections (cells did not travel farther than 1.5mm). These factors, in addition to the fact that there is no established nonhuman primate MTLE model in which to test MGE transplantation, make it unclear how these results may be translated to the human condition. It also should be noted that a gene therapy approach is an alternative solution for restoring inhibition in the epileptic brain that may avoid some of these limitations. Nonetheless, this work provides a significant step in evaluating the potential therapeutic role of inhibitory interneurons in the treatment of epilepsy.