Neuropharmacology of human TERA2.cl.SP12 stem cell-derived neurons in ultra-long-term culture for antiseizure drug discovery

Frontiers in Neuroscience

Neuroscience

Benjamin D. Zeitlin¹  Atefeh Rabiee²  Hamed Salmanzadeh²  Robert F. Halliwell²  Ankita Poojari² 

[1] Arthur A. Dugoni School of Dentistry, University of the Pacific, San Francisco, CA, United States;Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, United States;

关键词: multi electrode array;    anticonvulsants;    neural networks;    GABA receptors;    ionotropic glutamate receptors;    TERA2.cl.SP12 stem cells;   

DOI  :  10.3389/fnins.2023.1182720

 received in 2023-03-09, accepted in 2023-05-25,  发布年份 2023

来源: Frontiers

【 摘 要 】

Modeling the complex and prolonged development of the mammalian central nervous system in vitro remains a profound challenge. Most studies of human stem cell derived neurons are conducted over days to weeks and may or may not include glia. Here we have utilized a single human pluripotent stem cell line, TERA2.cl.SP12 to derive both neurons and glial cells and determined their differentiation and functional maturation over 1 year in culture together with their ability to display epileptiform activity in response to pro-convulsant agents and to detect antiseizure drug actions. Our experiments show that these human stem cells differentiate in vitro into mature neurons and glia cells and form inhibitory and excitatory synapses and integrated neural circuits over 6–8 months, paralleling early human neurogenesis in vivo; these neuroglia cultures display complex electrochemical signaling including high frequency trains of action potentials from single neurons, neural network bursts and highly synchronized, rhythmical firing patterns. Neural activity in our 2D neuron–glia circuits is modulated by a variety of voltage-gated and ligand-gated ion channel acting drugs and these actions were consistent in both young and highly mature neuron cultures. We also show for the first time that spontaneous and epileptiform activity is modulated by first, second and third generation antiseizure agents consistent with animal and human studies. Together, our observations strongly support the value of long-term human stem cell-derived neuroglial cultures in disease modeling and neuropsychiatric drug discovery.

【 授权许可】

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Copyright © 2023 Salmanzadeh, Poojari, Rabiee, Zeitlin and Halliwell.