Kinetics of GABAa Receptors in An Animal Model of Irradiation-induced Neuronal Migration Disorders

ABSTRACT

PURPOSE: A majority of patients with neuronal migration disorders(NMDs) in cortical structures suffer from medically intractable epilepsy. The role of NMDs on seizure susceptibility or epileptogenecity has not been well documented. In the present study, we established an experimental model of NMDs in Sprague-Dawley rats by exposing fetal rats to external irradiation in order to demonstrate epileptogenic effect of NMDs lesions. METHODS: Pregnant rats were exposed to 240cGy of external X-irradiation delivered by a linear accelerator source on gestational day 16 and 17 to produce NMDs lesions in rat brain. RESULTS: Microcephaly was evident on gross examination of the affected brains. Seizure susceptibility was tested by a small dose of kainate(0.1mg/kg) injected intraperitoneally, and the irradiated animals showed increased susceptibility to kainate. Histopathologic examination revealed cortical dysplasia consisting of dyslamination of cerebral cortex and appearance of cytomegalic neurons, neuronal heterotopia in periventricular white matter, dispersion of pyramidal layer and hippocampal dentate gyrus, and agenesis of corpus callosum. Histopathologic change of the cerebral cortex and hippocampus was closely correlated with seizure activity. Quantitative autoradiography of [H]muscimol binding to GABAA receptors was significantly reduced in NMDs lesions(P=0.02). CONCLUSION: In utero irradiation of fetal rats resulted in histopathologic abnormalities that mi- miced several characteristic features of human neuronal migration disorders, and hyperexcitability appears to be associated with reduction in density of GABAp receptors in the brain, particularly in hippocampus and neocortex.