Contribution of Aberrant GluK2-Containing Kainate Receptors to Chronic Seizures in Temporal Lobe Epilepsy

Abstract

Kainate is a potent neurotoxin known to induce acute seizures. However, whether kainate receptors (KARs) play any role in the pathophysiology of temporal lobe epilepsy (TLE) is not known. In TLE, recurrent mossy fiber (rMF) axons form abnormal excitatory synapses onto other dentate granule cells that operate via KARs. The present study explores the pathophysiological implications of KARs in generating recurrent seizures in chronic epilepsy. In an in vitro model of TLE, seizure-like activity was minimized in mice lacking the GluK2 subunit, which is a main component of aberrant synaptic KARs at rMF synapses. In vivo, the frequency of interictal spikes and ictal discharges was strongly reduced in GluK2(-/-) mice or in the presence of a GluK2/GluK5 receptor antagonist. Our data show that aberrant GluK2-containing KARs play a major role in the chronic seizures that characterize TLE and thus constitute a promising antiepileptic target.

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

“…It is thought that, in TLE models, glutamatergic neurotransmission is enhanced (Peret et al . ; Soukupova et al . ), whereas GABA release is decreased (Soukupova et al .…”

“…While the underlying cause of epilepsy remains largely unknown, current evidence supports a hypothesis in that an altered balance of excitatory and inhibitory circuits facilitates the occurrence of the first seizure episode, which in turn elicits cellular and molecular changes that may lower thresholds for sequential episodes. It is thought that, in TLE models, glutamatergic neurotransmission is enhanced (Peret et al 2014;Soukupova et al 2015), whereas GABA release is decreased (Soukupova et al 2014), leading to aberrant signaling and an overall increase in excitatory neuronal transmission. Furthermore, alterations in neuronal morphology, glial cells, and ECM have been related to the onset and development of epilepsy (Wetherington et al 2008;Quirico-Santos et al 2013;Singh et al 2013).…”

Depolarizing γ‐aminobutyric acid contributes to glutamatergic network rewiring in epilepsy

“…13 Statistical Analysis Data were expressed as mean 6 SEM. Tonic seizures were defined on the EEG as single or multiple 5 to 30Hz polyspikes of 5-fold standard deviation amplitude and 10-to 30-second duration.…”

Impaired neuronal operation through aberrant intrinsic plasticity in epilepsy

“…32,[35][36][37][38] This phenomenon, called reactive plasticity, is well documented in the dentate gyrus (DG), where dentate granule cell (DGC) axons (the mossy fibers [MFs]) sprout [35][36][37]39 and create a reverberant excitatory circuit between DGCs involved in epileptiform bursts in patients with TLE and animal models. 35,[40][41][42] Beyond epileptiform activities, 42 recurrent MF (rMF) synapses, which operate via kainate receptors (KARs) not present in naive conditions, 43 drive an aberrant sustained firing regime when recruited in the physiological gamma frequency range. 44 The long-lasting consequence of this local synaptopathic activity for the input-output operation of the major cortical input, the perforant path (PP), in DGCs remains to be addressed.…”