Medial Perforant Path Inhibition Mediated by mGluR7 Is Reduced After Status Epilepticus

Abstract

. Metabotropic glutamate receptor (mGluR)-mediated inhibition within the dentate gyrus is altered after epilepsy. Whether these changes occur during the developmental period of the disease (i.e., the latent period) has not yet been investigated. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the lateral (LPP) and medial perforant path (MPP) simultaneously in adult mouse hippocampal slices 3-9 days after pilocarpine (PILO)-induced status epilepticus. Genetically manipulated mice (mGluR8 knockout and mGluR4/8 double knockout) and pharmacologically selective agonists were used to identify specific mGluR subtypes affected after PILO. Pharmacological activation of mGluR7 by L-AP4 in both wild-type and mGluR4/8 double knockout mice selectively reduced fEPSPs in the MPP, but not LPP, and this level of inhibition was significantly reduced 3-9 days after PILO-induced SE. Activation of mGluR2/3 reversibly depressed the fEPSP slopes in both the MPP and LPP, but no alterations were noted after PILO. mGluR8 activation selectively inhibited evoked responses in the LPP, but not in the MPP, and this level of inhibition did not change after PILO treatment. These data suggest that reduced presynaptic inhibition mediated by mGluR7, but not mGluR2/3 or mGluR8, may play a role during the latent period in generating hyperexcitability in the dentate and thereby contribute to epileptogenesis.

Basement membrane protein nidogen‐1 shapes hippocampal synaptic plasticity and excitability

“…6; n 5 6). Here, they appeared as multiple after-discharges rather than single population spikes (Bough et al, 2004;Brenneke et al, 2004;Shao and Dudek, 2004). Again, such multiple spikes could not be evoked in wild-type slices (P 5 0.0,235, v 2 -test; n 5 6).…”

Agonists and Antagonists of Metabotropic Glutamate Receptors: Anticonvulsants and Antiepileptogenic Agents?

“…However, in neuronal elements of the basolateral amygdala in kindling model, and in the hippocampus of the rat and mouse pilocarpine models and of patients with mesial temporal lobe epilepsy, group II mGluRs were down regulated [34,64]. Decreased sensitivity to group III mGluR agonists in the lateral perforant path in kindling [24,29,37,40] and pilocarpine [13] models indicates the loss of feedback inhibition mediated by group III mGluRs, particularly that of subtype mGluR8 or mGluR7 respectively. It was supported by our study in the rat pilocarpine model showing drastic reduction of mGluR8 in the outer one-third of the molecular layer of the dentate gyrus [68].…”

“…A wealth of in vitro studies has suggested that agonists and antagonists of mGluRs could modulate epileptiform activity [13,24,35,40,48,49]. Parallel in vivo studies showed anticonvulsive effect of agonists and antagonists of mGluRs in different animal models ( Tables 1-4 or group II mGluR agonist 2R, 4R-APDC [64] were administered systemically during pilocarpine induced status epilepticus, no anticonvulsive effect was observed; it suggests that further studies have to be done before the conclusion that agonists and antagonists of mGluRs are antiepileptic is drawn.…”

Metabotropic glutamate receptors and epilepsy

“…During epileptogenesis in mice elicited by pilocarpine treatment, Bough et al [46] pointed out that mGluR mediated inhibition within the dentate gyrus (lateral perforant path, LPP; and medial perforant path, MPP) was altered after pilocarpine-induced status epilepticus (SE). Genetically manipulated mice (mGluR8 knockout and mGluR4/8 double knockout) and pharmacologically selective agonists were used to identify specific mGluR subtypes affected by pilocarpine.…”