Abstracts

Impaired hippocampal excitability constitutes a pathogenetic key aspect in temporal lobe epilepsy (TLE). Altered expressio) 5{of a variety of neurotransmitter receptors have been reported in human and experimental TLE. Metabotropic glutamate receptors (mGluRs) constitute a family of transmembrane domain receptors. Group III mGluRs (mGluR 4, 7 and 8) couple to cAMP-dependent signal transduction cascades, are localized presynaptically, and act to inhibit glutamate release at numerous central terminals. mGluR4 exhibits significantly increased expression in human epileptic dentate gyrus granule cells. Here, we have used mice with ablation of mGluR4 (mGluR4 KO) in order to study alterations with respect to hippocampal damage and the TLE phenotype. Status epilepticus (SE) was induced by systemic application of pilocarpine to mGluR4 ablated as well as control mGluR4 +/+ mice. Seizure susceptibility was determined after induction of SE. The frequency and severity of chronic recurrent seizures is currently analyzed with a telemetric EEG system (DSI) and parallel video analysis. In order to study hippocampal damage, the amount of segmental hippocampal loss of neurons and gliosis were analyzed in mGluR4 KO mice after SE. Using real time quantitative RT-PCR, compensatory expression alterations of other mGluRs are excluded. mGluR4 KO mice exhibit a significantly reduced survival in response to pilocarpine treatment (mGluR4 KO 31 %, n = 16, vs. controls 56 %, n = 9; p [lt] 0.001). Preliminary data indicate a higher incidence of stage IV seizures in mGluR4 KO mice after SE compared to controls. Histopathological comparisons revealed increased neuronal cell loss and gliosis in all observed hippocampal subfields in mGluR4 KO (CA1: mGluR4 KO 54 % , controls 79 %, p [lt] 0.05; DG: mGluR4 KO 40 %, controls 74 %, p [lt] 0,05; CA3 + CA4: mGluR4 KO 34 % , controls 65 %, p [lt] 0,001; mGluR4 n = 3; control n = 5). Our results indicate mGluR4 to be correlated with an attenuated epileptic phenotype and hippocampal damage. These data underline mGluRs to constitute interesting targets in order to interfere with hippocampal damage and epileptic attacks in TLE. (Supported by DFG (SFB TR3) and BONFOR)