RESUMO
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.
Assuntos
Neocórtex/fisiologia , Neurônios/fisiologia , Receptores de GABA-A/fisiologia , Animais , Animais Recém-Nascidos/fisiologia , Antimetabólitos , Bicuculina/farmacologia , Bromodesoxiuridina , Cálcio/metabolismo , Cálcio/fisiologia , Movimento Celular , Implantes de Medicamento , Eletrofisiologia , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Técnicas In Vitro , Cinética , Muscimol/farmacologia , Neocórtex/citologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Glutamate plays an important role in the control of neuronal migration in the developing cerebral cortex. The present study describes changes in the structure and function of the cerebral cortex after transient blockade of N-methyl-D-aspartate (NMDA) receptors during the late period of neuronal migration. Elvax slices containing the NMDA antagonist MK801 were placed over the somatosensory cortex of newborn rats and the drug was released over a period of 2-3 days. After survival times of 1 or 2 weeks, neuroanatomical and in vitro electrophysiological analyses revealed prominent structural and functional alterations in the cortical region underlying the implant. Cortical lamination was disturbed and heterotopic cell clusters were found in layer I of MK801-treated animals. Morphologically identified pyramidal neurons recorded in MK801-treated cortex revealed late NMDA receptor-mediated synaptic inputs and fragile monosynaptic responses at stimulation frequencies >0.2 Hz. Our data indicate that impairment of NMDA receptors during early corticogenesis induces neuronal migration disorders and delays the functional maturation of the developing cortical network.