GABA-A receptors regulate neocortical neuronal migration in vitro and in vivo

Nicolas Heck, Werner Kilb, Petra Reiprich, Hisahiko Kubota, Tomonori Furukawa, Atsuo Fukuda, Heiko J. Luhmann

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)

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 μM) and muscimol (1 and 10 μM), 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 μM muscimol) or blockade (10 μM) 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.

Original languageEnglish
Pages (from-to)138-148
Number of pages11
JournalCerebral Cortex
Volume17
Issue number1
DOIs
Publication statusPublished - 2007 Jan

Keywords

  • GABA-A receptor
  • In vitro
  • In vivo
  • Intracellular calcium
  • Neuronal migration

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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