Aberrant axonal reorganization and altered distribution of
neurotransmitter receptor subtypes have been proposed as major pathogenic mechanisms for hippocampal hyperexcitability in chronic
temporal lobe epilepsies (TLE). Recent data point to excitatory class I
metabotropic glutamate receptors (
mGluR1 and mGluR5) as interesting candidates. Here, we have analyzed the hippocampal distribution and
mRNA expression of
mGluR1 and mGluR5 in two rat models of limbic
seizures, i.e. electrical kindling and intraperitoneal
kainate injections, as well as in human TLE. Quantitative RT-PCR analysis detected a significant increase of hippocampal
mGluR1 gene transcript levels in
kainate treated and kindled rats. In addition, microdissected hippocampal tissue samples localized this increase to the dentate gyrus. Using immunohistochemistry with mGluR1alpha subtype specific
antibodies, increased labeling was observed within the dentate gyrus molecular layer (DG-ML). A similar pattern of increased mGluR1alpha neuropil staining was found within the DG-ML of
epilepsy patients (n = 42) compared with peritumoral hippocampus specimens obtained from nonepileptic patients (biopsy controls, n = 3). This increase was detected in TLE patients with segmental hippocampal cell loss, as well as in TLE patients with focal lesions but no histopathological alterations of the hippocampus. In contrast, mGluR5 immunoreactivity and
mRNA expression were not significantly altered in the DG-ML. Our data demonstrate a striking regional induction of mGluR1alpha in the hippocampal dentate gyrus of experimental animals with limbic
seizures as well as in human patients with chronic, intractable TLE. This increase corresponds to functional alterations of class I mGluRs observed in seizure models and may significantly contribute to hippocampal hyperexcitability in focal human
epilepsies.