TY - JOUR
T1 - In vitro electrophysiological drug testing on neuronal networks derived from human induced pluripotent stem cells
AU - Parodi, Giulia
AU - Zanini, Giorgia
AU - Collo, Linda
AU - Impollonia, Roberta
AU - Cervetto, Chiara
AU - Frega, Monica
AU - Chiappalone, Michela
AU - Martinoia, Sergio
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/11/17
Y1 - 2024/11/17
N2 - Background: In vitro models for drug testing constitute a valuable and simplified in-vivo-like assay to better comprehend the biological drugs effect. In particular, the combination of neuronal cultures with Micro-Electrode Arrays (MEAs) constitutes a reliable system to investigate the effect of drugs aimed at manipulating the neural activity and causing controlled changes in the electrophysiology. While chemical modulation in rodents’ models has been extensively studied in the literature, electrophysiological variations caused by chemical modulation on neuronal networks derived from human induced pluripotent stem cells (hiPSCs) still lack a thorough characterization. Methods: In this work, we created three different configurations of hiPSCs-derived neuronal networks composed of fully glutamatergic neurons (100E), 75% of glutamatergic and 25% of GABAergic neurons (75E25I) and fully GABAergic neurons (100I). We focused on the effects caused by antagonists of three of the most relevant ionotropic receptors of the human brain, i.e., 2-amino-5-phosphonovaleric (APV, NMDA receptors antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, AMPA receptors antagonist), and bicuculline, picrotoxin and pentylenetetrazole (BIC, PTX, and PTZ, respectively, GABAA receptors antagonists). Results: We found that APV and CNQX completely abolished the network bursting activity and caused major changes in the functional connectivity. On the other hand, the effect of BIC, PTX and PTZ mostly affected configurations in which the inhibitory component was present by increasing the firing and network bursting activity as well as the functional connectivity. Conclusions: Our work revealed that hiPSCs-derived neuronal networks are very sensitive to pharmacological manipulation of the excitatory ionotropic glutamatergic and inhibitory ionotropic GABAergic transmission, representing a preliminary and necessary step forward in the field of drug testing that can rely on pathological networks of human origin.
AB - Background: In vitro models for drug testing constitute a valuable and simplified in-vivo-like assay to better comprehend the biological drugs effect. In particular, the combination of neuronal cultures with Micro-Electrode Arrays (MEAs) constitutes a reliable system to investigate the effect of drugs aimed at manipulating the neural activity and causing controlled changes in the electrophysiology. While chemical modulation in rodents’ models has been extensively studied in the literature, electrophysiological variations caused by chemical modulation on neuronal networks derived from human induced pluripotent stem cells (hiPSCs) still lack a thorough characterization. Methods: In this work, we created three different configurations of hiPSCs-derived neuronal networks composed of fully glutamatergic neurons (100E), 75% of glutamatergic and 25% of GABAergic neurons (75E25I) and fully GABAergic neurons (100I). We focused on the effects caused by antagonists of three of the most relevant ionotropic receptors of the human brain, i.e., 2-amino-5-phosphonovaleric (APV, NMDA receptors antagonist), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, AMPA receptors antagonist), and bicuculline, picrotoxin and pentylenetetrazole (BIC, PTX, and PTZ, respectively, GABAA receptors antagonists). Results: We found that APV and CNQX completely abolished the network bursting activity and caused major changes in the functional connectivity. On the other hand, the effect of BIC, PTX and PTZ mostly affected configurations in which the inhibitory component was present by increasing the firing and network bursting activity as well as the functional connectivity. Conclusions: Our work revealed that hiPSCs-derived neuronal networks are very sensitive to pharmacological manipulation of the excitatory ionotropic glutamatergic and inhibitory ionotropic GABAergic transmission, representing a preliminary and necessary step forward in the field of drug testing that can rely on pathological networks of human origin.
KW - Drug testing
KW - Electrophysiology
KW - Human induced pluripotent stem cells
KW - Micro-Electrode Arrays
UR - https://www.scopus.com/pages/publications/85209576112
U2 - 10.1186/s13287-024-04018-2
DO - 10.1186/s13287-024-04018-2
M3 - Article
C2 - 39551784
AN - SCOPUS:85209576112
SN - 1757-6512
VL - 15
JO - Stem Cell Research and Therapy
JF - Stem Cell Research and Therapy
IS - 1
M1 - 433
ER -