Glutamate receptors in dysplasic cortex: an in situ hybridization and immunohistochemistry study in rats with prenatal treatment with methylazoxymethanol.

Injection of the antimitotic drug methylazoxymethanol (MAM) in the pregnant rat at E14 leads in the offsprings to a severe malformation with microcephaly and cortical heterotopiae in the white matter and in the CA1 field of the hippocampus. These animals suffer cognitive and epileptic disorders. Since these pathologies have been associated with glutamatergic transmission abnormalities, we have examined by in situ hybridization and immunohistochemistry the distribution and expression levels of several glutamate receptors subunits in these rats. Examination of the GluR2 flip and flop, NR1, NR2A and NR2B subunit gene transcripts showed a qualitatively similar distribution in both the neocortex and hippocampus of MAM and control rats. Quantitative analysis revealed an altered proportion of the GluR2 flip and flop subunits in the CA1 region of MAM animals as compared to controls. Moreover, a 26% reduction in the expression of the NR1 subunit and a 40% increase in the expression of the GluR2 flip subunit were noted in cortical heterotopiae, as compared to the adjacent neocortex. Immunostaining for GluR2/3, NR1 or NR2 showed, in both MAM and control animals, that glutamate receptors were mainly concentrated in the soma and dendrites of neocortical and hippocampal pyramidal cells, including in heterotopiae, and in the apical dendrites of hippocampal granule cells. Abnormalities in the expression of glutamate receptor subtypes in cortical heterotopiae and in the hippocampal CA1 region could contribute to functional disorders previously reported in MAM animals such as memory impairments and epilepsy.