Arrest of neuronal migration by excitatory amino acids in hamster developing brain

Abstract

The inf luence of the excitotoxic cascade on the developing brain was investigated using ibotenate, a glutamatergic agonist of both N-methyl-D-aspartate (NMDA) ionotropic receptors and metabotropic receptors. Injected in the neopallium of the golden hamster at the time of production of neurons normally destined for layers IV, III, and II, ibotenate induces arrests of migrating neurons at different distances from the germinative zone within the radial migratory corridors. The resulting cytoarchitectonic patterns include periventricular nodular heterotopias, subcortical band heterotopias, and intracortical arrests of migrating neurons. The radial glial cells and the extracellular matrix are free of detectable damage that could suggest a defect in their guiding role. The migration disorders are prevented by coinjection of DL-2-amino-7-phosphoheptanoic acid, an NMDA ionotropic antagonist, but are not prevented by coinjection of L(؉)-2-amino-3-phosphonopropionic acid, a metabotropic antagonist. This implies that an excess of ionic inf lux through the NMDA channels of neurons alters the metabolic pathways supporting neuronal migration. Ibotenate, a unique molecular trigger of the excitotoxic cascade, produces a wide spectrum of abnormal neuronal migration patterns recognized in mammals, including the neocortical deviations encountered in the human brain.In targeted postmigratory neurons, excitatory amino acids trigger a calcium-dependent death (1-4). At each developmental step after completion of neocortical neuronal migration, the excitotoxic cascade produces a timed set of laminar and multilaminar neuronal depopulations. It mimics all lesional brain patterns described after hypoxia occurring in human fetuses and neonates between 20 and 40 weeks of gestation (3-6). In contrast, no excitotoxic destructive effect has been reported before maturation of N-methyl-D-aspartate (NMDA) receptors and before acquisition of postmigratory neuronal aerobiosis. In seminal observations performed in organotypic tissue cultures, Komuro and Rakic (7) reported accelerations and decelerations of cerebellar neuronal migration under the influence of excitatory amino acids. The present paper reports neuronal migration disorders induced in vivo in hamster by ibotenate, a glutamatergic agonist, and uses this model to approach the pathophysiology of these frequent neurodevelopmental disturbances. MATERIALS AND METHODSAnimal Handling and Injections of Ibotenate and of Other Glutamatergic Agents. Golden hamsters were chosen for this study because of the timing of brain development in this species. As regards neuronal migration in the neopallium, the newborn hamster is at a stage similar to that of the human fetus at 15 weeks of gestation and at a stage comparable to that of the mouse at the 17th embryonic day. Pregnant female golden hamsters were allowed to deliver on day 16 of gestation. Several successive litters of newborn hamsters of both sexes were used for the experiments. Ibotenate, a glutamatergic agonist, activates both NMDA ion...

Distribution of Glutamate Transporter Subtypes During Human Brain Development

“…These studies have shown that granule cell migration is dependent on Ca 2~influx through the NMDA subtype of glutamate receptors in cerebellar slices. A different study also demonstrated that excessive stimulation of NMDA receptors disturbed neuronal migration (Marret et al, 1996). Therefore, removal of glutamate by EAAT2 may play an important role during neuronal migration toward the cortex by modulating NMDA receptor activation.…”

Ectopic parvalbumin expression in mouse forebrain neurons increases excitotoxic injury provoked by ibotenic acid injection into the striatum

“…IBO is an agonist of glutamate (Zorumski et al, 1989). It induces neurodegeneration by activation of the NMDA receptors (Marret et al, 1996) and by coactivation of the metabotropic glutamate receptors, mediating the release of Ca 2+ from intracellular stores. This results in well-demarcated lesions (Inglis and Semba, 1997), which can be easily compared in wildtype mice (WT) and transgenic mice.…”

El síndrome de Kuzniecky

“…La polimicrogiria generalmente resulta de algún desorden en el desarrollo o algún tipo de injuria a la corteza durante su desarrollo, al final de la migración cortical o al inicio de la organización cortical 5,6 ; esta alteración en el desarrollo de la corteza aparentemente tiene una tendencia genética, como lo muestra este síndrome.…”