Animal model of excitotoxic lesions during brain development

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Glutamate is the main excitotoxin during development. Among the different types of ionotropic glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor mediates a large part of excitotoxic neuronal injury during development. Glutamate metabotropic receptors have been reported to stimulate phosphoinositide hydrolysis and to potentiate the NMDA effects.

Different glutamate agonists have been used to produce excitotoxic brain damage, both during development and in the adult rodent. In particular, ibotenate, an agonist of the N-methyl-D-aspartate (NMDA) complex receptor and of the group I metabotropic receptor, has been used to study the spectrum of excitotoxic disturbances at different ages of cerebral development.

During maturation of neuronal layer V and during migration of neurons destined to granular and supragranular layers, newborn hamsters intracerebrally injected at P0 with ibotenate display arrests of migrating neurons at different distances from the germinative zone [11]. High doses of ibotenate induce periventricular and subcortical neuronal heterotopias while low doses of ibotenate produce intracortical heterotopias and molecular layer ectopias. The resulting cytoarchitectonic patterns mimic some migration disorders encountered in humans [12, 13].

After completion of neuronal layer V and during the full settlement of supragranular layers, P0 mice and rats injected with ibotenate disclosed a laminar neuronal depopulation of layer V-VIa sharply mimicking human microgyria [14-16].

Injected after completion of migration (P5-P10 in mouse or rat), ibotenate produced a neuronal loss in all neocortical layers [14], mimicking neocortical lesions occurring in the term human newborns. Furthermore, at this developmental stage, ibotenate induced the formation of white matter cysts, mimicking some aspects of periventricular white matter observed in human preterm infants [17].