Emerging neurotrophic role of GABAB receptors in neuronal circuit development

Abstract

The proper development of highly organized structures in the central nervous system is a complex process during which key events - neurogenesis, migration, growth, differentiation, and synaptogenesis - have to take place in an appropriate manner to create functional neuronal networks. It is now well established that GABA, the main inhibitory neurotransmitter in the adult mammalian brain, plays more than a classical inhibitory role and can function as an important developmental signal early in life. GABA binds to chloride-permeable ionotropic GABAA receptors and to G-protein-coupled GABAB receptors (GABAB-Rs). Although most of the trophic actions of GABA have been attributed to the activation of GABAA receptors, recent advances show that GABAB-Rs also regulate fundamental steps of network development. This review summarizes some of the recent progress about the neurotrophic role of GABAB-Rs to neuronal development.

Keywords: GABA; GABAB receptors; cortical development; migration; synaptogenesis.

FIGURE 1

GABA_B-Rs modulate radial and tangential migration. (A) E15 brain slices were cut at 300 μm and 4-chloromethyl benzoyl amino tetramethyl rhodamine (CMTMR)-coated particles were placed in the medial ganglionic eminence (MGE) of each hemisphere to label the tangentially migratory neurons. The slices were then incubated for 24 h in vitro in normal culture medium (a,c) or in the presence of 1 μM of the GABA_BR antagonist, CGP52432 (b,d). After the incubation period, the slices were fixed and counterstained with 0.002% bis-benzimide (blue) to reveal the different cortical compartments and brain structures. In control conditions more CMTMR-labeled cells located at the lower intermediate zone (LIZ) were observed (c) while in the presence of CGP52432 the majority of CMTMR-labeled cells were observed in the ventricular/subventricular zones (VZ/SVZ; d). Asterisks at (c,d) represent where the majority of the CMTMR-positive cells were localized. Abbreviations: ctx, cortex; LIZ, lower intermediate zone; mz, marginal zone; VZ, ventricular zone. Scale bars: a,b 200 μm, c,d 100 μm. Modified with permission from Lopez-Bendito et al. (2003). (B) Confocal images of tdTomato fluorescence in coronal sections of rat somatosensory cortices P16 after in utero transfection (at E17) with pRNAT-U6.3 (EGFP) siRNA empty vector together with pCAG-IRES-tdTomato (Tomato, Control), or functional GABA_B2-siRNA (siRNA) together with Tomato construct. Dotted white lines delimitate the boundaries of the cortical layers. Note the presence of ectopic neurons that did not complete radial migration in the layers V and VI. Scale bar: 150 μm. LII–LIV, layer II–IV; WM, white matter. Modified with permission from Bony et al. (2013).

FIGURE 2

GABA_B-Rs modulate GABAergic synaptogenesis and plasticity. The activation of GABA_B-Rs induces the formation of diacylglycerol (DAG), activation of protein kinase C (PKC), and the opening of L-type voltage-dependent Ca²⁺ channels (L-VDCC). The intracellular Ca²⁺ rise triggers the secretion of BDNF which acting on TrkB-Rs modulate the formation and efficacy of developing GABAergic synapses.