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

Abstract

Selective hippocampal cell loss and altered neurotransmitter receptor expression have been proposed as pathogenic mechanisms in the development of chronic mesial temporal lobe epilepsy (TLE). Studies in animal models point to metabotropic glutamate receptors (mGluRs) as modulators of hippocampal epileptogenesis. In addition, mGluRs may constitute specific targets for the development of novel anticonvulsive drugs. As mGluR4 represents an inhibitory class III mGluR associated with the reduction of intracellular cyclic AMP levels and calcium influx, we have analyzed the regional and cellular expression of mGluR4 in surgical hippocampal specimens obtained from patients with TLE by using immunohistochemistry and in situ hybridization. Although the hippocampi of control specimens (n = 11) were almost devoid of mGluR4 immunolabeling, all TLE specimens (n = 35) showed a striking up‐regulation of mGluR4 immunoreactivity, in particular within the dentate gyrus. Immunoelectron microscopy localized the receptor protein to the periphery of presynaptic and postsynaptic membranes. In situ hybridization revealed increased transcript levels of mGluR4 in dentate granule cells and residual CA4 neurons of TLE specimens compared with controls. Our results suggest a potential role of mGluR4 in counteracting excitatory hippocampal activity and in modulating 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. Ann Neurol 2000; 47:26–35

Metabotropic glutamate receptors and epilepsy

“…Lie et al [37] found an up-regulation of mGluR4 (group III) immunoreactivity in particular within the dentate gyrus. These results have suggested a role for mGluR4 in counteracting excitatory hippocampal activity.…”

Metabotropic Glutamate Receptor Subtypes as Targets for Neuroprotective Drugs

“…Similar to group-I antagonists or group-II agonists, group-III mGlu receptor agonists exert anticonvulsant activity (Abdul-Ghani et al, 1997;Tang et al, 1997;Chapman et al, 1999;Gasparini et al, 1999a;Claudio et al, 2000). Although these effects are common to many drugs, a growing body of evidence suggests that mGlu4 receptors are directly involved in the pathophysiology of epilepsy (Lie et al, 2000).…”

“…Pentylenetetrazol-induced seizures lead to an increase in (3H)-L-AP4 binding in the cerebral cortex (Thomsen, 1999), whereas electrical kindling is associated with a lower ability of group-III mGlu receptor agonists to inhibit transmission at the lateral perforant path-dentate gyrus synapses (Klapstein et al, 1999). Human studies show that mGlu4 receptors are up-regulated in dentate granule cells and CA4 neurons in surgical hippocampal specimen obtained from patients with temporal lobe epilepsy (Lie et al, 2000), whereas a reduced function of L-AP4-sensitive mGlu receptors is observed in the epileptic sclerotic hippocampus (Dietrich et al, 1999). An attractive hypothesis is that seizure vulnerability of distinct neuronal populations is regulated by the levels of expression and function of mGlu4 receptors.…”

Comparative proteomics and correlated signaling network of rat hippocampus in the pilocarpine model of temporal lobe epilepsy

“…Because a favorable response to unilateral temporal lobe resection is observed in .75% of patients and the typical pathologic abnormality is hippo-campal neuronal loss and gliosis [2], and moreover hippocampal sclerosis is found in the TLE patients that is recapitulated in animal models of TLE [3], much attention has been paid to the epileptogenic hippocampus. Not only the role of hippocampal neurogenesis in physiological and pathological conditions has been intensely investigated [4], but also several mechanisms that are responsible for hippocampal injury and subsequent epileptogenesis have been proposed, which include events that are largely a consequence of activation of the N-methyl-D-aspartate (NMDA) receptor [5,6] and the metabotropic glutamate receptors (mGluRs) [7][8][9].…”