Modularity and neuronal heterogeneity: Two properties that influence in vitro neuropharmacological experiments

Martina Brofiga; Fabio Poggio; Francesca Callegari; Mariateresa Tedesco; Paolo Massobrio

doi:10.3389/fncel.2023.1147381

Modularity and neuronal heterogeneity: Two properties that influence in vitro neuropharmacological experiments

Front Cell Neurosci. 2023 Mar 20:17:1147381. doi: 10.3389/fncel.2023.1147381. eCollection 2023.

Authors

Martina Brofiga^{1

2}, Fabio Poggio¹, Francesca Callegari¹, Mariateresa Tedesco³, Paolo Massobrio^{1

4

5}

Affiliations

¹ Department of Informatics, Bioengineering, Robotics, and Systems Engineering (DIBRIS), University of Genova, Genova, Italy.
² ScreenNeuroPharm S.r.l., Sanremo, Italy.
³ 3Brain GmbH, Wädenswil, Switzerland.
⁴ National Institute for Nuclear Physics (INFN), Genova, Italy.
⁵ MNESYS Extended Partnership Neuroscience and Neuropharmacology, Genova, Italy.

Abstract

Introduction: The goal of this work is to prove the relevance of the experimental model (in vitro neuronal networks in this study) when drug-delivery testing is performed.

Methods: We used dissociated cortical and hippocampal neurons coupled to Micro-Electrode Arrays (MEAs) arranged in different configurations characterized by modularity (i.e., the presence of interconnected sub-networks) and heterogeneity (i.e., the co-existence of neurons coming from brain districts). We delivered increasing concentrations of bicuculline (BIC), a neuromodulator acting on the GABAergic system, and we extracted the IC₅₀ values (i.e., the effective concentration yielding a reduction in the response by 50%) of the mean firing rate for each configuration.

Results: We found significant lower values of the IC₅₀ computed for modular cortical-hippocampal ensembles than isolated cortical or hippocampal ones.

Discussion: Although tested with a specific neuromodulator, this work aims at proving the relevance of ad hoc experimental models to perform neuropharmacological experiments to avoid errors of overestimation/underestimation leading to biased information in the characterization of the effects of a drug on neuronal networks.

Keywords: bicuculline; cortical neurons; dose-response curve; hippocampal neurons; interconnected brain-regions-on-a-chip; micro-electrode arrays (MEAs); neuromodulation.

Grants and funding

This work was carried out within the framework of the project “MNESYS – A multiscale integrated approach to the study of the nervous system in health and disease” and has been supported by European Union – NextGenerationEU.