A kainic acid-induced seizure model in human pluripotent stem cell-derived cortical neurons for studying the role of IL-6 in the functional activity

Stem cell research

article

Ropafadzo Mzezewa¹  Johanna Lotila¹  Heikki Kiiski²  Andrey Vinogradov¹  Fikret Emre Kapucu¹  Jukka Peltola³  Sanna Hagman¹  Susanna Narkilahti¹ 

[1] Neuro Group, Faculty of Medicine and Health Technology, Tampere University;Tampere University Hospital, Department of Intensive Care;Department of Neurology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University

关键词: Cortical neurons;    Disease modeling;    Interleukin 6;    Human pluripotent stem cells;    Microelectrode arrays;    Seizures;   

DOI  :  10.1016/j.scr.2022.102665

学科分类：生理学

来源: Academic Press

【 摘 要 】

Human pluripotent stem cell (hPSC)-derived neural cultures have attracted interest for modeling epilepsy and seizure-like activity in vitro. Clinical and experimental evidence have shown that the multifunctional inflammatory cytokine interleukin (IL)-6 plays a significant role in epilepsy. However, the role of IL-6 in neuronal networks remains unclear. In this study, we modelled seizure-like activity in hPSC-derived cortical neurons using kainic acid (KA) and explored the effects of IL-6 and its counterpart, hyper-IL-6 (H-IL-6), a fusion protein consisting of IL-6 and its soluble receptor, IL-6R. In the seizure-like model, functionally mature neuronal networks responded to KA induction with an increased bursting phenotype at the single electrode level, while network level bursts decreased. The IL-6 receptors, IL6R and gp130 , were expressed in hPSC-derived cortical neurons, and the gene expression of IL6R increased during maturation. Furthermore, the expression of IL-6R increased not only after IL-6 and H-IL-6 treatment but also after KA treatment. Stimulation with IL-6 or H-IL-6 was not toxic to the neurons and cytokine pretreatment did not independently modulate neuronal network activity or KA-induced seizures. Furthermore, the increased expression of IL-6R in response to IL-6, H-IL-6 and KA implies that neurons can respond through both classical and trans-signaling pathways. Acute treatment with IL-6 and H-IL-6 did not alter functional activity, suggesting that IL-6 does not affect the induction or modulation of newly induced seizures in healthy cultures. Overall, we propose this model as a useful tool to study seizure-like activity in neuronal networks in vitro.

【 授权许可】

CC BY|CC BY-NC-ND