Human Cortical Interneurons Optimized for Grafting Specifically Integrate, Abort Seizures, and Display Prolonged Efficacy Without Over-Inhibition

Authors

Qian Zhu, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Akanksha Mishra, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Joy S. Park, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Dongxin Liu, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.Follow
Derek T. Le, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Sasha Z. Gonzalez, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Morgan Anderson-Crannage, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.Follow
James M. Park, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Gun-Hoo Park, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Laura Tarbay, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Kamron Daneshvar, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Matthew Brandenburg, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Christina Signoretti, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Amy Zinski, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Edward-James Gardner, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Kelvin L. Zheng, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Chiderah P. Abani, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.Follow
Carla Hu, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Cameron P. Beaudreault, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.
Xiao-Lei Zhang, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.Follow
Patric K. Stanton, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA.Follow
Jun-Hyeong Cho, Department of Molecular, Cell and Systems Biology, University of California, Riverside, Riverside, CA, USA.Follow
Libor Velíšek, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA; Department of Neurology, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA; Department of Pediatrics, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA.
Jana Velíšková, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA; Department of Neurology, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA; Department of Obstetrics & Gynecology New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA.
Saqlain Javed, Department of Physiology, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA.
Christopher S. Leonard, Department of Physiology, New York Medical College, Valhalla, Mount Pleasant, NY 01595, USA.Follow
Hae-Young Kim, Department of Public Health, New York Medical College, Valhalla, Mount Pleasant, NY, USA.Follow
Sangmi Chung, Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 01595, USA. Electronic address: schung8@nymc.edu.Follow

Author Type(s)

Faculty

DOI

10.1016/j.neuron.2022.12.014

Journal Title

Neuron

First Page

807

Last Page

823.e7

Document Type

Article

Publication Date

3-15-2023

Department

Cell Biology and Anatomy

Second Department

Physiology

Third Department

Public Health

Abstract

Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy.

Recommended Citation

Zhu, Q., Mishra, A., Park, J. S., Liu, D., Le, D. T., Gonzalez, S. Z., Anderson-Crannage, M., Park, J. M., Park, G., Tarbay, L., Daneshvar, K., Brandenburg, M., Signoretti, C., Zinski, A., Gardner, E., Zheng, K. L., Abani, C. P., Hu, C., Beaudreault, C. P., Zhang, X., Stanton, P. K., Cho, J., Velíšek, L., Velíšková, J., Javed, S., Leonard, C. S., Kim, H., & Chung, S. (2023). Human Cortical Interneurons Optimized for Grafting Specifically Integrate, Abort Seizures, and Display Prolonged Efficacy Without Over-Inhibition. Neuron, 111 (6), 807-823.e7. https://doi.org/10.1016/j.neuron.2022.12.014