GABA system as the cause and effect in early development

Abstract

GABA is the primary inhibitory neurotransmitter in the adult brain and through its actions on GABA_ARs, it protects against excitotoxicity and seizure activity, ensures temporal fidelity of neurotransmission, and regulates concerted rhythmic activity of neuronal populations. In the developing brain, the development of GABAergic neurons precedes that of glutamatergic neurons and the GABA system serves as a guide and framework for the development of other brain systems. Despite this early start, the maturation of the GABA system also continues well into the early postnatal period. In this review, we organize evidence around two scenarios based on the essential and protracted nature of GABA system development: 1) disruptions in the development of the GABA system can lead to large scale disruptions in other developmental processes (i.e., GABA as the cause), 2) protracted maturation of this system makes it vulnerable to the effects of developmental insults (i.e., GABA as the effect). While ample evidence supports the importance of GABA/GABA_AR system in both scenarios, large gaps in existing knowledge prevent strong mechanistic conclusions.

Keywords: Early development; Early life stress; Fetal alcohol syndrome; GABA; GABAA receptors; Maternal immune activation.

Fig 1.. The GABAA receptor.

Side (A), top (B), and zoomed-in (C) illustration of the GABAA receptor. Composed of five subunits, GABAA receptors are heterotetrameric Cys-loop ligand-gated ion channels (A). Each subunit is composed of four transmembrane domains (TM), a long extracellular N-terminal domain, and a short extracellular C-terminal domain (B, C).

Fig 2.. Neocortex GABAergic neurons.

Schematics of some major interneuron types and interneuron connectivity across cortical layers.

Fig 3.. Maternal immune activation.

Schematics of the maternal immune activation (MIA) model and a summary of the effects of MIA on GABAergic developmental processes.