Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human pluripotent stem cells (hPSCs) has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that hPSC-derived maturing GABAergic interneurons (mGINs) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness, and hyperactivity. These results provide support for the potential of hPSC-derived mGIN for restorative cell therapy for epilepsy.
Some Salient Discussions:
- The paper reports that the stem cell derived neurons homes in CA3, CA1 & DG, whereas prior work from our department reported significant localisation in the DG. Host immunity could play a role, as the latter was done on relatively immuno-competent rats.
- Could developmental/maturational changes in channel rhodopsin impact the results of Optogenetic stimulation experiments reported in the paper?
- Is immaturity of the stem-cell derived GABA neurons the critical factor in the success of this approach?
- The immunosuppression of rats described in the study could have contributed to the success of the approach, but may add further challenges in the clinical setting as well as the pathogenesis of Epilepsy.