Reduced function of L-AP4-sensitive metabotropic glutamate receptors in human epileptic sclerotic hippocampus

Human temporal lobe epilepsy is characterized by strong synaptic reorganiza tion that leads to abnormal recurrent excitatory synaptic connections among hippocampal neurons. In addition, electrophysiological studies show that s ynaptic activity of the main afferent input to the hippocampus, the perfora nt path, is prolonged and amplified by changes in postsynaptic glutamate re ceptors. The current view is that these morphological and physiological abn ormalities contribute significantly to the hyperexcitability seen in the hi ppocampus of temporal lobe epilepsy Recently, it was found that presynaptic inhibitory metabotropic glutamate receptors are an important negative feed back mechanism that controls synaptic release of glutamate in the hippocamp us. In this study we assessed the functionality of this feedback system by investigating the metabotropic glutamate receptor mediated depression of ex citatory synaptic transmission in surgically removed hippocampi from patien ts with marked synaptic reorganization (Ammon's horn sclerosis group) and f rom patients without detectable reorganization (lesion group). We report he re that this control of synaptic transmission is lost in hippocampi from th e Ammon's horn sclerosis group whereas this control is preserved in hippoca mpi from the lesion group. The data presented here suggest that the loss of feedback inhibition mediated by metabotropic glutamate receptors could be a further, previously not recognized, mechanism in the pathophysiology of t emporal lobe epilepsy.