A Human iPSC-Derived Neuron and Glioma Culture Model Reveals Increased Neuronal Excitability and Loss of GABAergic Inhibition
Abstract
Gliomas engage in bidirectional interactions with neural circuits, driving hyperexcitability, disruption of excitatory-inhibitory balance, and tumor-associated seizures. Human in vitro models that enable functional interrogation of tumor-induced changes in glutamatergic-GABAergic neuronal crosstalk remain limited. We established a defined human induced pluripotent stem cell (iPSC)-derived culture comprising of glutamatergic neurons, GABAergic neurons, and astrocytes with and without glioma cells. Network maturation and function were characterized using immunocytochemistry, multi-electrode array recordings, and whole-cell patch-clamp electrophysiology. Neuronal cultures developed mature synaptic architecture, spontaneous coordinated network activity, and suppression of neuronal firing following treatment with the GABA-A agonist muscimol, demonstrating functional GABAergic signaling. Glioma incorporation increased spike rate, increased coordinated network activity, and reversed the response to muscimol from suppression to elevation of neuronal firing, indicating disrupted GABAergic signaling. Whole-cell patch-clamp recordings demonstrated increased intrinsic excitability of glutamatergic neurons following glioma co-culture, characterized by increased action potential firing frequency and increased action potential amplitude. This human iPSC-derived glutamatergic–GABAergic neuron model recapitulates key features of tumor-induced neuronal dysfunction while enabling complementary network- and single-cell analyses. The model provides a relevant, scalable, and accessible system for mechanistic investigation of bidirectional neuron–glioma interactions and preclinical evaluation of therapies targeting tumor-induced neuronal dysfunction.
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BibTeX
@misc{haile2026human,
title = {{A Human iPSC-Derived Neuron and Glioma Culture Model Reveals Increased Neuronal Excitability and Loss of GABAergic Inhibition}},
author = {Hannah Haile and Brianna Pereira and Jacqueline Niu and Karen Conboy and Sandra Leskinen and Angeliki Mela and Athanassios Dovas and August Kahle and Abby L. Brand and Ashwin Viswanathan and Nelson Humala and Aayushi Mahajan and Tasneem Meem and Roland A. Scott and Anthony J. Tang and Misha Amini and Wisdom Yevudza and Christopher D. Makinson and Jeffrey N. Bruce and Catherine Schevon and Henry Colecraft and Peter Canoll and Brian J. A. Gill},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11002745/v1},
url = {https://doi.org/10.21203/rs.3.rs-11002745/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - A Human iPSC-Derived Neuron and Glioma Culture Model Reveals Increased Neuronal Excitability and Loss of GABAergic Inhibition
AU - Hannah Haile
AU - Brianna Pereira
AU - Jacqueline Niu
AU - Karen Conboy
AU - Sandra Leskinen
AU - Angeliki Mela
AU - Athanassios Dovas
AU - August Kahle
AU - Abby L. Brand
AU - Ashwin Viswanathan
AU - Nelson Humala
AU - Aayushi Mahajan
AU - Tasneem Meem
AU - Roland A. Scott
AU - Anthony J. Tang
AU - Misha Amini
AU - Wisdom Yevudza
AU - Christopher D. Makinson
AU - Jeffrey N. Bruce
AU - Catherine Schevon
AU - Henry Colecraft
AU - Peter Canoll
AU - Brian J. A. Gill
PY - 2026
DA - 2026/10/12
PB - Research Square
DO - 10.21203/rs.3.rs-11002745/v1
UR - https://doi.org/10.21203/rs.3.rs-11002745/v1
AB - Gliomas engage in bidirectional interactions with neural circuits, driving hyperexcitability, disruption of excitatory-inhibitory balance, and tumor-associated seizures. Human in vitro models that enable functional interrogation of tumor-induced changes in glutamatergic-GABAergic neuronal crosstalk remain limited. We established a defined human induced pluripotent stem cell (iPSC)-derived culture comprising of glutamatergic neurons, GABAergic neurons, and astrocytes with and without glioma cells. Network maturation and function were characterized using immunocytochemistry, multi-electrode array recordings, and whole-cell patch-clamp electrophysiology. Neuronal cultures developed mature synaptic architecture, spontaneous coordinated network activity, and suppression of neuronal firing following treatment with the GABA-A agonist muscimol, demonstrating functional GABAergic signaling. Glioma incorporation increased spike rate, increased coordinated network activity, and reversed the response to muscimol from suppression to elevation of neuronal firing, indicating disrupted GABAergic signaling. Whole-cell patch-clamp recordings demonstrated increased intrinsic excitability of glutamatergic neurons following glioma co-culture, characterized by increased action potential firing frequency and increased action potential amplitude. This human iPSC-derived glutamatergic–GABAergic neuron model recapitulates key features of tumor-induced neuronal dysfunction while enabling complementary network- and single-cell analyses. The model provides a relevant, scalable, and accessible system for mechanistic investigation of bidirectional neuron–glioma interactions and preclinical evaluation of therapies targeting tumor-induced neuronal dysfunction.
SN - 2693-5015
ER -