ABSTRACT
GABA is the main inhibitory neurotransmitter in adults. Depolarizing/excitatory GABA responses have been well characterized at the level of neuronal-population average during typical neurodevelopment and partially in pathology. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing/excitatory or hyperpolarizing/inhibitory GABAergic responses exists in adult animals in health/disease. Here, we showed that such mosaicism is present both in adult WT and Down syndrome (DS) mice, as assessed at increasing scales of neuronal-network complexity (cultures, brain- slices, behaving mice). Nevertheless, WT mice presented a 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. We also found heterogeneous GABAergic responses in mature control and trisomic human iPSC-derived neurons. Thus, a heterogeneous population of GABA-responding cells exists in physiological/pathological conditions in mature mouse and human neurons, possibly contributing to disease-associated behaviours.
Competing Interest Statement
LC is the cofounder and a scientific advisor at IAMA Therapeutics. LC and AC are inventors on the following patents: US 9,822,368 (granted 2017); EP 3083959 (granted 2019); JP 6490077 (granted 2019) and US 11427836 (granted 2022), US 17/861676, EP 18717045.1, HK 62020014163.3, CA 3059389, CN 201880038547.7, JP 2020-505522, and IL 269952.