GABA-A Receptors Regulate Neocortical Neuronal Migration In Vitro and In Vivo

Abstract

The cortical migration process depends on a number of trophic factors and on the activation of different voltage- and ligand-gated channels. We investigated the role of gamma-aminobutyric acid (GABA) type A receptors in the neuronal migration process of the newborn rat parietal cortex in vivo and in vitro. Local in vivo application of the GABA-A antagonist bicuculline methiodide (BMI) or the agonist muscimol via cortical surface Elvax implants induced prominent alterations in the cortical architecture when compared with untreated or sham-operated controls. BMI- and muscimol-treated animals revealed heterotopic cell clusters in the upper layers and a complete loss of the cortical lamination in the region underlying the Elvax implant. Immunocytochemical staining for glial fibrillary acidic protein, N-methyl-D-aspartate receptors, and GABA demonstrated that heterotopia was not provoked by glial proliferation and confirmed the presence of both glutamatergic and GABAergic neurons. In organotypic neocortical slices from embryonic day 18-19 embryos, application of BMI and to a lesser extent also muscimol induced an increase in the migration speed and an accumulation of neurons in the upper cortical layers. Spontaneous intracellular calcium ([Ca2+]i) oscillations in neocortical slices from newborn rats were abolished by BMI (5 and 20 microM) and muscimol (1 and 10 microM), indicating that both compounds interfere with [Ca2+]i signaling required for normal neuronal migration. Electrophysiological recordings from migrating neurons in newborn rat neocortical slices indicate that long-term application of muscimol causes a pronounced reduction (1 microM muscimol) or blockade (10 microM) in the responsiveness of postsynaptic GABA-A receptors due to a pronounced receptor desensitization. Our results indicate that modulation of GABA-A receptors by compounds acting as agonists or antagonists may profoundly influence the neuronal migration process in the developing cerebral cortex.

GABA and glutamate signaling: homeostatic control of adult forebrain neurogenesis

“…However, two recent studies provide some additional support for this finding. Heck et al (2007) found that application of the GABA A receptor antagonist, bicuculline, induced an increase in the migration speed of cortical neurons in organotypic neocortical slices from embryonic day 18-19. This increase in speed resulted in aberrant accumulation of neurons in the upper cortical layers.…”

GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

“…Local in vivo application of bicuculline methiodide via cortical surface Elvax implants revealed heterotopic cell clusters in the upper layers (264). In organotypic neocortical slices from embryonic day 18 -19 embryos, bicuculline increased the migration speed, suggesting an inhibitory action of GABA on migration (264).…”

GABA Regulates Excitatory Synapse Formation in the Neocortex via NMDA Receptor Activation

“…Of particular interest is the role of neurotransmitters in the regulation of activity-dependent mechanisms of synaptogenesis. During corticogenesis, the principal adult inhibitory neurotransmitter GABA influences the processes of cell proliferation, migration, and differentiation (Barbin et al, 1993;LoTurco et al, 1995;Heck et al, 2007). GABAergic signaling precedes glutamatergic signaling in the developing neocortex because newborn neurons express GABA A receptors (GABA A Rs) and receive GABAergic inputs from striatally derived interneurons before forming glutamatergic synapses with each other (Owens et al, 1999;Hennou et al, 2002).…”