Resources
Authors & Affiliations
Aurore Ribera, Guillaume Cinquanta, Jacques Barik, Laeticia Davidovic, Olfa Khalfallah, Paula Pousinha
Abstract
Studying human brain development has remained difficult as appropriate models lack. Recently, induced pluripotent stem cells (iPSC)-derived 3D brain organoids have been developed. They recapitulate the key aspects of human brain development such as the cellular complexity and functional properties of specific regions. Yet, longitudinal functional studies are sparse. During neurodevelopment in vivo, GABAergic inhibitory interneurons from the ventral cortex migrate to populate the dorsal part of the cortex enriched in glutamatergic excitatory neurons (Zhu et al. Neuron, 1999; Le et al., JBC, 2007). This migration is critical to reach an optimal excitatory/inhibitory balance in the cortex. We aimed at assessing longitudinally (from D60 to D300) the maturation and functionality of GABAergic neurons in dorsal/ventral organoids and assembloids, using patch-clamp electrophysiological recordings. We analysed intrinsic passive properties, intrinsic excitability and spontaneous excitatory transmission. We observed a developmental stage-dependant evolution of the resting membrane potential. It decreases over time indicating a progressive neuronal maturation. Action potentials were detected at different time points depending on the ventro-dorsal differentiation of the organoids, suggesting differences between glutamatergic and GABAergic neurons development. Spontaneous excitatory transmission was also recorded and correlated with the developmental stage. We noticed that neurons in assembloids or in ventral organoids presented intrinsic excitability at earlier developmental stages, suggesting the need of GABAergic cells to the maturation of glutamatergic cells. Overall, this research contributes to our understanding of human brain development and uncovers the potential of iPSC-derived brain organoids as valuable tools for studying neurodevelopmental processes.