Temporal lobe epilepsy associated up-regulation of metabotropic glutamate receptors: Correlated changes in mGluR1 mRNA and protein expression in experimental animals and human patients

Aberrant axonal reorganization and altered distribution of neurotransmitter receptor subtypes have been proposed as major pathogenic mechanisms for hi ppocampal hyperexcitability in chronic temporal lobe epilepsies (TLE). Rece nt data point to excitatory class I metabotropic glutamate receptors (mGluR 1 and mGluR5) as interesting candidates. Here, we have analyzed the hippoca mpal distribution and mRNA expression of mGluR1 and mGluR5 in two rat model s 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 kain ate treated and kindled rats. In addition, microdissected hippocampal tissu e samples localized this increase to the dentate gyrus. Using immunohistoch emistry with mGluR1 alpha subtype specific antibodies, increased labeling w as observed within the dentate gyrus molecular layer (DG-ML). A similar pat tern of increased mGluR1 alpha neuropil staining was found within the DG-ML of epilepsy patients (n = 42) compared with peritumoral hippocampus specim ens obtained from nonepileptic patients (biopsy controls, n = 3). This incr ease was detected in TLE patients with segmental hippocampal cell loss, as well as in TLE patients with focal lesions but no histopathological alterat ions of the hippocampus. In contrast, mGluR5 immunoreactivity and mRNA expr ession were nor significantly altered in the DG-ML. Our data demonstrate a striking regional induction of mGluR1 alpha in the hippocampal dentate gyru s of experimental animals with limbic seizures as well as in human patients with chronic, intractable TLE. This increase corresponds to functional alt erations of class I mGluRs observed in seizure models and may significantly contribute to hippocampal hyperexcitability in focal human epilepsies.