GABAA receptors, anesthetics and anticonvulsants in brain development

Abstract

GABA, acting via GABA(A) receptors, is well-accepted as the main inhibitory neurotransmitter of the mature brain, where it dampens neuronal excitability. The receptor's properties have been studied extensively, yielding important information about its structure, pharmacology, and regulation that are summarized in this review. Several GABAergic drugs have been commonly used as anesthetics, sedatives, and anticonvulsants for decades. However, findings that GABA has critical functions in brain development, in particular during the late embryonic and neonatal period, raise worthwhile questions regarding the side effects of GABAergic drugs that may lead to long-term cognitive deficits. Here, we will review some of these drugs in parallel with the control of CNS development that GABA exerts via activation of GABA(A) receptors. This review aims to provide a basic science and clinical perspective on the function of GABA and related pharmaceuticals acting at GABA(A) receptors.

Fig. (1). GABA_A receptor structure and location of drug binding sites

(A) Diagram illustrating the pentameric structure of GABA_A receptors containing 2α, 2β and 1γ subunits. (B) Schematic illustration of the α6 subunit with its three domains (extracellular, transmembrane and intracellular) and binding sites for GABA and other drugs. (C) Diagram illustrating the binding sites of different GABAergic drugs.

Fig. (2). Diagram of the developing zones where GABA regulates cell development

(A) Schematic representation of an embryonic (E) 15 coronal section of the forebrain. Radial glia (RG, green) proliferate in the ventricular zone (VZ) and extend their processes to the pial surface across the ganglionic eminence and the neocortex. Neuronal precursors (blue) migrate along radial glial processes and some proliferate in the SVZ (not shown on the diagram). Both proliferation and migration are regulated by GABA (#1-3). The migration of the precursors of cortical GABAergic interneurons (orange) born in the VZ of the ganglionic eminence is also affected by GABA (#4). S: primordia of septum, H: primordia of hippocampus. (B) Schematic representation of an adult sagittal section of the forebrain illustrating the neurogenic zones, the SVZ along the lateral ventricle and the subgranular zone (SGZ). GABA decreases the proliferation of neural progenitors and neuroblasts in the SVZ (#5), and the speed of migration of neuroblasts (#6) on their way to the olfactory bulb. (C) Simplified lineage summary.