NMDA receptor-mediated long-term alterations in epileptiform activity in experimental chronic epilepsy

Abstract

When epileptiform activity is acutely induced in vitro, transient partial blockade of N-methyl-Daspartic acid (NMDA) receptor-mediated calcium influx leads to selective long-term depotentiation of the synapses involved in the epileptic activity as well as a reduction in the probability of further epileptiform activity. If such selective depotentiation occurred within foci of epileptic activity in vivo, the corresponding long-term reduction in seizure probability could form the basis for a novel treatment of epilepsy. Continuous radiotelemetric EEG monitoring demonstrated modest acute anticonvulsant effects but no long-term reductions in the probability of spontaneous seizures after transient partial blockade of NMDA receptors (NMDAR) during ictal and interictal activity in the kainate animal model of chronic epilepsy. In vitro, depotentiation was induced when NMDAR were partially blocked during epileptiform activity in hippocampal slices from control animals, but not in slices from chronically epileptic rats. However in slices from epileptic animals, depotentiation during epileptiform activity was induced by partial block of NMDAR using NR2B but not NR2A selective antagonists. These results suggest that chronic epileptic activity is associated with changes in NMDA receptor-mediated signaling that is reflected in the pharmacology of activity-and NMDA receptordependent depotentiation.

The Calcineurin Inhibitor Ascomicin Interferes with the Early Stage of the Epileptogenic Process Induced by Latrunculin A Microperfusion in Rat Hippocampus

“…On the other hand, PP2B inhibition might also have its effects over several brain receptors function and composition. This effect was also previously described in other animal models (Hellier et al 2009;Lau and Zukin 2007), and resulted to be modified after ASC action in our model. The postsynaptic density is rich in PP2B, and NMDA receptor, AMPA/kainate glutamate receptors, and GABAA receptor have been identified as either direct or indirect substrates regulated by PP2B.…”

Kainic Acid Treatment Increases Ca2+-mediated Neurotoxicity in the Mouse Hippocampus

“…It has been reported that phosphorylated NMDA receptor subtype 2B (NR2B) can increase Ca 2+ permeability through NMDA receptors [30]. NR2B has been identified as an indicator of intracellular Ca 2+ influx that is activated by seizures [31].…”

Sensing-enabled hippocampal deep brain stimulation in idiopathic nonhuman primate epilepsy

“…Another challenge is that the mechanism of seizure generation, and therefore response to potential therapeutic interventions, is still poorly understood and may vary between subjects. While suppression of local activity within a seizure focus might be intended to serve as a functional lesion, network regulation and long-term plasticity have also been hypothesized as potential seizure suppression mechanisms (Hellier et al 2009). In contrast to the ability to manipulate the clinical stimulation device in our epileptic NHP over multiple experiments, human studies of direct hippocampal stimulation have almost exclusively branched from an initial report of 10 patients undergoing intracranial monitoring.…”