Defining the role of GABA in cortical development

Abstract

Of the many signals in the developing nervous system, GABA (gamma-aminobutyric acid) has been shown to be one of the earliest neurotransmitters present. Unlike in the adult, where this transmitter acts synaptically to inhibit neurons, during development, GABA can depolarize progenitor cells and their progeny due to their high intracellular chloride concentration. This early form of GABA signalling may provide the main excitatory drive for the immature cortical network and play a central role in regulating cortical development. Many features of GABA signalling are conserved in different species and are recapitulated during neurogenesis in the adult brain, demonstrating the importance of this versatile molecule in driving cortical formation. Here, we present recent evidence supporting the multiple functions of GABA during embryonic development and adult neurogenesis, from regulating progenitor proliferation to influencing the migration and maturation of newborn neurons.

Figure 2. GABA's role in adult neurogenesis in the subventricular zone (A) and the dentate gyrus of the hippocampus (B)

A, in this adult neurogenic niche, astrocytes divide asymmetrically to give rise to intermediate progenitors (IPC), which divide again to generate immature neurons. These immature neurons produce GABA, which activates GABA_A receptors in the subventricular zone astrocytes and depolarizes their membrane to negatively regulate their proliferation. GABA produced by the young neurons decreases their migration to the rostral migratory stream (RMS), where they will eventually become granule cells or periglomerular cells in the olfactory bulb. B, astrocytes of the subgranular zone are the stem cells that can produce IPCs through asymmetrical division. These IPCs generate immature neurons, which express GABA_A receptors and respond tonically to GABA released from local interneurons. GABA-mediated depolarization regulates the synaptic maturation and integration of granule cells into the existing circuit, allowing them to receive inhibitory inputs from hilar interneurons and excitatory glutamatergic inputs from the lateral and medial perforant pathways. LV: lateral ventricle; EP: ependymal cell layer; SVZ: subventricular zone: SGZ: subgranular zone; GCL: granule cell layer; DG: dentate gyrus; ML: molecular layer; MPP: medial perforant pathway; LPP: lateral perforant pathway; SR: stratum radiatum.

Figure 1. GABA's role in regulating embryonic cortical development

During corticogenesis, interneurons migrating in the subventricular zone (SVZ) can release GABA and activate GABA_A receptors on the radial glia, depolarizing these progenitors and decreasing their proliferation. Radial glia generates immature pyramidal neurons through asymmetrical division, and the migration of these immature neurons along the radial fibres is decreased by GABA signalling. As young neurons assume their position in the cortex and begin to mature, GABA-mediated depolarization by the interneurons is required for the development of dendritic arbors and excitatory synaptic inputs from other pyramidal neurons. MZ: marginal zone; VZ: ventricular zone; SVZ: subventricular zone; CP: cortical plate.