Up-regulation of the metabotropic glutamate receptor mGluR4 in hippocampalneurons with reduced seizure vulnerability

Selective hippocampal cell loss and altered neurotransmitter receptor expre ssion have been proposed as pathogenic mechanisms in the development of chr onic mesial temporal lobe epilepsy (TLE). Studies in animal models point to metabotropic glutamate receptors (mGluRs) as modulators of hippocampal epi leptogenesis. In addition, mGluRs may constitute specific targets for the d evelopment of novel anticonvulsive drugs. As mGluR4 represents an inhibitor y class III mGluR associated with the reduction of intracellular cyclic AMP levels and calcium influx, we have analyzed the regional and cellular expr ession of mGluR4 in surgical hippocampal specimens obtained from patients w ith TLE by using immunohistochemistry and in situ hybridization. Although t he hippocampi of control specimens (n = 11) were almost devoid of mGluR4 im munolabeling, all TLE specimens (n = 35) showed a striking up-regulation of mGluR4 immunoreactivity, in particular within the dentate gyrus. Immunoele ctron microscopy localized the receptor protein to the periphery of presyna ptic and postsynaptic membranes. In situ hybridization revealed increased t ranscript levels of mGluR4 in dentate granule cells and residual CA4 neuron s of TLE specimens compared with controls. Our results suggest a potential role of mGluR4 in counteracting excitatory hippocampal activity and in modu lating seizure-associated vulnerability of hippocampal neurons. These data may also provide a basis for pharmacological studies of mGluR4 agonists as potential novel drugs in the treatment of TLE.