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Heterogeneous subpopulations of GABAAR-responding neurons coexist across neuronal networks scales and developmental stages in health and disease

iScience - A Cell Press Journal

Authors: I. Colombi, M. Rastogi, M. Parrini, M. Alberti, A. Potenzieri, M. Chelali, S. Rosati, M. Chiappalone, M. Nanni, A. Contestabile, L. Cancedda
Publication: iScience
Date: March 8, 2024
Link to article: https://www.sciencedirect.com/science/article/pii/S258900422400659X


GABA is the main inhibitory neurotransmitter in adults. Depolarizing GABA responses have been well characterized at neuronal-population average level during typical neurodevelopment and partially in brain disorders. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing or hyperpolarizing/inhibitory GABAergic responses exists in animals in health/disease at diverse developmental stages, including adulthood. Here, we showed that such mosaicism is present in WT and Down syndrome (DS) neuronal-networks, as assessed at increasing scales of complexity (cultures, brain-slices, behaving mice). Nevertheless, WT mice presented a much-lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behaviour in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human iPSC-derived neurons. Thus, a heterogeneous subpopulation of GABA-responding cells exists in physiological/pathological conditions in mouse and human neurons, possibly contributing to disease-associated behaviours.

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