Anya Ittiruck

Background: Epilepsy is a neurological condition affecting 50-60 million people worldwide characterized by seizures^1,2. Seizure type can be further subdivided into generalized, focal, and epileptic spasm with temporal lobe epilepsy (TLE) being the most common form of the focal subdivision^2,3. Mesial temporal lobe epilepsy (mTLE) is the most common form of TLE in which seizures involve the hippocampus, entorhinal cortex, amygdala, and parahippocampal gyrus³. There are many probable causes for epilepsy, however, 50% of cases of epilepsy are idiopathic¹. Astroglial glutamine synthetase dysfunction has been linked to focal epilepsy phatogenesis⁶. Glutamine synthetase in an enzyme highly abundant in astrocytes and is important in the glutamine-glutamate-GABA cycle which metabolizes glutamate, the predominant excitatory neurotransmitter typically associated with mTLE, and produces GABA needed for inhibitory neurotransmission⁶. While many treatments have been effective in treating epilepsy, stem cell research has shown promising remarks in treating TLE by grafting inhibitory GABA-ergic neurons into the brain to dampen the effects of synchronized firing^2,5.

Objective: In this review, the grafting of GABAergic inhibitory interneurons was explored in its effectiveness for treating mesial temporal lobe epilepsy.

Search Methods: Using PubMed, an online word search including “Stem cell therapy”, “Temporal Lobe Epilepsy” and further extending into “pathology”, “etiology” and “treatment” was conducted, filtering for the years 2018-2023.

Results: In a hESC derived hMGE model of differentiated GABAergic interneurons in TLE induced animal, a 76% reduction in spontaneous recurrent seizures was observed using EEG video recordings⁵. In another study implementing the same method to introduce GABAergic interneurons into a TLE model, 72% of the transplanted animals saw at least a 75% decrease in seizure activity with 59% being seizure free 7 months post transplant¹⁰. In two studies utilizing hMGE derived GABAergic interneurons method, object location tests (OLT) and pattern separation tests were utilized to observe and compare cognitive function between naïve, grafted status epilepticus (SE) induced, and non-grafted SE induced animal models^5,13. The OLT and PST showed marked improvement in cognitive function, pattern recognition, memory as well as other tests concluding improvement in motivation deficits and anhedonia^5,13. In order to test efficacy of the graft itself, designer receptor exclusively activated by designer drugs (DREADDs) is a method used to silence the grafted interneurons⁵. With this graft silencing, a marked increase in spontaneous recurrent seizure activity and time spent in seizure activity substantially increased, as well as cognitive function reversion occurred. While turning off this silencing, seizure activity returned to pre-CNO injection levels⁵.

Conclusion: Grafting stem cell or astroglia derived GABAergic interneurons has seen efficacy in animal models for decreasing seizure activity and improving cognitive function in TLE models^5,10,13. This research has been foundational as support for potential new treatment for drug resistant epilepsy³. There are now ongoing clinical trials for this kind of therapy in temporal lobe epilepsy, including one current human trial.

Works Cited:

1.  Falco-Walter J. Epilepsy-Definition, Classification, Pathophysiology, and Epidemiology. Semin Neurol. 2020;40(6):617-623. doi:10.1055/s-0040-1718719
2. Alayli A, Lockard G, Gordon J, et al. Stem Cells: Recent Developments Redefining Epilepsy Therapy. Cell Transplantation. 2023;32. doi:10.1177/09636897231158967
3. Vinti V, Dell’Isola GB, Tascini G, et al. Temporal Lobe Epilepsy and Psychiatric Comorbidity. Front Neurol. 2021;12:775781. Published 2021 Nov 30. doi:10.3389/fneur.2021.775781
4. Beghi E. The Epidemiology of Epilepsy. Neuroepidemiology. 2020;54(2):185-191. doi:10.1159/000503831
5. Upadhya D, Attaluri S, Liu Y, Hattiangady B, Castro OW, Shuai B, Dong Y, Zhang SC, Shetty AK. Grafted hPSC-derived GABA-ergic interneurons regulate seizures and specific cognitive function in temporal lobe epilepsy.NPJ Regenerative Medicine, 7(1):38, 2022.
6. Sandhu MRS, Gruenbaum BF, Gruenbaum SE, et al. Astroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy. Front Neurol. 2021;12:665334. Published 2021 Apr 13. doi:10.3389/fner.2021.665334
7. Mesraoua B, Brigo F, Lattanzi S, Abou-Khalil B, Al Hail H, Asadi-Pooya AA. Drug-resistant epilepsy: Definition, pathophysiology, and management. J Neurol Sci. 2023;452:120766. doi:10.1016/j.jns.2023.120766
8. Taraschenko O, Pavuluri S, Schmidt CM, Pulluru YR, Gupta N. Seizure burden and neuropsychological outcomes of new-onset refractory status epilepticus: Systematic review. Front Neurol. 2023;14:1095061. Published 2023 Jan 24. doi:10.3389/fneur.2023.1095061
9. Lentini C, d’Orange M, Marichal N, et al. Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy. Cell Stem Cell. 2021;28(12):2104-2121.e10. doi:10.1016/j.stem.2021.09.002
10. Bershteyn M, Bröer S, Parekh M, et al. Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy. Cell Stem Cell. 2023;30(10):1331-1350.e11. doi:10.1016/j.stem.2023.08.013
11. Zhu Q, Mishra A, Park JS, et al. Human cortical interneurons optimized for grafting specifically integrate, abort seizures, and display prolonged efficacy without over-inhibition. Neuron. 2023;111(6):807-823.e7. doi:10.1016/j.neuron.2022.12.014
12. Upadhya D, Hattiangady B, Castro OW, et al. Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration. Proc Natl Acad Sci U S A. 2019;116(1):287-296. doi:10.1073/pnas.18141851