iScience (Apr 2024)

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

  • Ilaria Colombi,
  • Mohit Rastogi,
  • Martina Parrini,
  • Micol Alberti,
  • Alberto Potenzieri,
  • Mariam Marie Chellali,
  • Silvia Rosati,
  • Michela Chiappalone,
  • Marina Nanni,
  • Andrea Contestabile,
  • Laura Cancedda

Journal volume & issue
Vol. 27, no. 4
p. 109438

Abstract

Read online

Summary: Gamma-aminobutyric acid (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 wild-type (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 behavior in DS mice. Moreover, we found heterogeneous GABAergic responses in developed control and trisomic human induced-pluripotent-stem-cells-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 behaviors.

Keywords