Activation of the GABA_A Receptor Inhibits the Proliferative Effects of bFGF in Cortical Progenitor Cells

Abstract

Recent studies have localized gamma-aminobutyric acid (GABA)-containing neurons and identified cells that express subunits of the GABAA receptor in the proliferative zone of the developing cerebral cortex and have demonstrated a role for GABA in cortical neurogenesis. We examined here the interactions between a number of neurotrophic factors, known to be involved in cortical cell proliferation and differentiation, and the GABAergic system (GABA and GABAA receptors) in the regulation of cell production in dissociated cortical cell cultures. We found that basic fibroblast growth factor (bFGF) increased the number of cells labelled for the alpha 1 subunit of the GABAA receptor but not for the alpha 2, alpha 3 or alpha 5 subunits. The alpha 1 subunit was expressed by the majority of proliferating neuroepithelial cells as well as by differentiated neurons. We also found that activation of the GABAA receptor by GABA or muscimol inhibited the proliferative effects of bFGF on cortical progenitors, leading to an increased number of differentiated neurons. These results suggest that bFGF stimulates cell proliferation and GABAA receptor expression in cultured progenitor cells of the developing neocortex, and that GABA regulates cell production by providing a feedback signal that terminates cell division.

Cell Coupling and Uncoupling in the Ventricular Zone of Developing Neocortex

“…Such factors include the amino acid neurotransmitters GABA and glutamate that reduce the number of VZ cells in S phase (L oT urco et al, 1995) and basic FGF (bFGF) that increases proliferation of neocortical precursors (Ghosh and Greenberg, 1995). A recent paper has demonstrated that GABA can counter the proliferative effects of bFGF, suggesting an interaction between these distinct signaling systems (Antonopoulos et al, 1997).…”

“…Such factors include the amino acid neurotransmitters GABA and glutamate that reduce the number of VZ cells in S phase (L oT urco et al, 1995) and basic FGF (bFGF) that increases proliferation of neocortical precursors (Ghosh and Greenberg, 1995). A recent paper has demonstrated that GABA can counter the proliferative effects of bFGF, suggesting an interaction between these distinct signaling systems (Antonopoulos et al, 1997).In addition to interacting with extracellular diffusible factors, cells within the VZ can interact directly with each other by intercellular coupling (LoTurco and Kriegstein, 1991). The function of cell coupling in the VZ is not known; however, gap junction communication among cells has been shown to be an important regulator of development in other systems (Guthrie and Gilula, 1989).…”

Neurogenesis Mediated by γ-Aminobutyric Acid and Glutamate Signaling

“…The neurotransmitters GABA and glutamate are shown to reduce the number of proliferating cells in dissociated or organotypic cultures of rat neocortex (19). GABA partially blocks the bFGFinduced increase in cell proliferation (20), but promotes cell proliferation in cultures of rat cerebellar progenitors (21). Signals mediated by ionotropic GABA A R are shown to promote neuronal differentiation after depolarization in neural progenitors of adult mouse hippocampal slices (22).…”

Regulation of neuroblast mitosis is determined by PACAP receptor isoform expression

“…T he production of new neurons, or neurogenesis, is controlled in part by locally secreted factors that regulate proliferation (1)(2)(3)(4)(5). Ligands for G protein-coupled receptors (GPCR) may play significant roles in neurogenesis in a regionally or developmentally specific fashion (6)(7)(8)(9).…”