S. Marret et al., EFFECT OF IBOTENATE ON BRAIN-DEVELOPMENT - AN EXCITOTOXIC MOUSE MODELOF MICROGYRIA AND POSTHYPOXIC-LIKE LESIONS, Journal of neuropathology and experimental neurology, 54(3), 1995, pp. 358-370
Ibotenate, a glutamatergic agonist, was injected in developing mouse n
eopallium. When injected at the time of completion of supragranular ne
uronal migration (P0) ibotenate induces complete neuronal depopulation
of layers V-VI and an abnormal sulcation of the overlying supragranul
ar layers. Injected after completion of migration (P5-P10) ibotenate p
roduces severe neuronal loss in layers II, III, IV, V, and VI. After e
xposure to ibotenate between P0 and P5, surviving neurons have the abi
lity to resume their migration, inducing an abnormal neocortical patte
rn. Periventricular white matter lesions are observed after ibotenate
injection at P2-P10, with a peak of occurrence at P5. Both gray and wh
ite matter damage are prevented by DL-2-amino-7-phosphonoheptanoic aci
d, an N-methyl-D-aspartate receptor antagonist, but not by L (+)-2-ami
no-3-phosphonopropionic acid, a metabotropic glutamate receptor antago
nist. The microtubule-associated type 2 protein, a dendritic marker, i
s absent in all ibotenate lesions, which reflects the developmental im
pairment of the dendritic phase. These staged lesions of the gray and
white matter disclose a developmental sequence of excitotoxin-affected
events starting with the selective and layered sensitivity of postmig
ratory neocortical neurons and continuing in the white matter with the
astroglial maturation and the axonal growth. They faithfully mimic mi
crogyrias, focal cortico-subcortical dysplasias, porencephalic cysts,
and white matter damage observed in human perinatal hypoxic/ischemic l
esions. This mouse model provides tools for investigating excitotoxic
influences on neural development at the various stages and for identif
ying protective substances against excitotoxicity from hypoxic and fro
m nonhypoxic origins.