Epileptiform GluN2B–driven excitation in hippocampus as a therapeutic target against temporal lobe epilepsy

NMDAR is an ionotropic glutamate receptor critically involved in excitatory synaptic transmission. The receptor properties are strongly determined by its subunit composition. One of the NMDAR subunits is GluN2B, which displays restricted and spatially different from other subunits expression in the mature brain. GluN2B–containing NMDARs are present in the hippocampus – a structure playing a major role in temporal lobe epilepsy (TLE). However, the contribution of GluN2B to pathophysiology of TLE has not been fully explored. Here, we report the functional alterations of GluN2B–containing NMDAR receptors in the hippocampus in distinct mouse models of temporal lobe epilepsy. In particular, we show the impact of GluN2B on excitatory feedback in granule cells. Based on these results, we propose a mechanism–oriented effective antiepileptic strategy that selectively antagonizes GluN2B–containing NMDARs with ifenprodil, a well–known GluN2B antagonist. Collectively, our research identifies GluN2B as one of the pivotal factors in pathogenesis of temporal lobe epilepsy and associated recurrent seizures. Furthermore, our study indicates the prospective antiepileptic properties of ifenprodil in TLE.

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Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.02.133 ◽

2012 ◽

Vol 420 (1) ◽

pp. 156-160 ◽

Cited By ~ 22

Author(s):

Rainer Surges ◽

Maria Kukley ◽

Amy Brewster ◽

Christiane Rüschenschmidt ◽

Johannes Schramm ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Cation Current

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Altered A-type potassium channel function in the nucleus tractus solitarii in acquired temporal lobe epilepsy

Journal of Neurophysiology ◽

10.1152/jn.00556.2018 ◽

2019 ◽

Vol 121 (1) ◽

pp. 177-187 ◽

Cited By ~ 1

Author(s):

Isabel D. Derera ◽

Katalin Cs. Smith ◽

Bret N. Smith

Keyword(s):

Temporal Lobe Epilepsy ◽

Mouse Models ◽

Temporal Lobe ◽

Neuronal Excitability ◽

Gabaergic Neurons ◽

Nucleus Tractus Solitarii ◽

Sudden Unexpected Death ◽

Inactivation Kinetics ◽

Unexpected Death ◽

Increased Risk

Sudden unexpected death in epilepsy (SUDEP) is among the leading causes of death in people with epilepsy. Individuals with temporal lobe epilepsy (TLE) have a high risk for SUDEP because the seizures are often medically intractable. Neurons in the nucleus tractus solitarii (NTS) have been implicated in mouse models of SUDEP and play a critical role in modulating cardiorespiratory and autonomic output. Increased neuronal excitability of inhibitory, GABAergic neurons in the NTS develops during epileptogenesis, and NTS dysfunction has been implicated in mouse models of SUDEP. In this study we used the pilocarpine-induced status epilepticus model of TLE (i.e., pilo-SE mice) to investigate the A-type voltage-gated K+ channel as a potential contributor to increased excitability in GABAergic NTS neurons during epileptogenesis. Compared with age-matched control mice, pilo-SE mice displayed an increase in spontaneous action potential frequency and half-width 9–12 wk after treatment. Activity of GABAergic NTS neurons from pilo-SE mice showed less sensitivity to 4-aminopyridine. Correspondingly, reduced A-type K+ current amplitude was detected in these neurons, with no change in activation or inactivation kinetics. No changes were observed in Kv4.1, Kv4.2, Kv4.3, KChIP1, KChIP3, or KChIP4 mRNA expression. These changes contribute to the increased excitability in GABAergic NTS neurons that develops in TLE and may provide insight into potential mechanisms contributing to the increased risk for cardiorespiratory collapse and SUDEP in this model. NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in epilepsy, and dysfunction in central autonomic neurons may play a role. In a mouse model of acquired epilepsy, GABAergic neurons in the nucleus tractus solitarii developed a reduced amplitude of the A-type current, which contributes to the increased excitability seen in these neurons during epileptogenesis. Neuronal excitability changes in inhibitory central vagal circuitry may increase the risk for cardiorespiratory collapse and SUDEP.

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The Impact of Right Temporal Lobe Epilepsy On Nonverbal Memory: Meta-regression of Stimulus- and Task-related Moderators

Neuropsychology Review ◽

10.1007/s11065-021-09514-3 ◽

2021 ◽

Author(s):

Adam C. Bentvelzen ◽

Roy P. C. Kessels ◽

Nicholas A. Badcock ◽

Greg Savage

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Nonverbal Memory ◽

Meta Regression ◽

Right Temporal Lobe Epilepsy ◽

The Impact ◽

And Task

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Astrocytic BDNF and TrkB regulate severity and neuronal activity in mouse models of temporal lobe epilepsy

Cell Death and Disease ◽

10.1038/s41419-020-2615-9 ◽

2020 ◽

Vol 11 (6) ◽

Cited By ~ 1

Author(s):

Sara Fernández-García ◽

Anna Sancho-Balsells ◽

Sophie Longueville ◽

Denis Hervé ◽

Agnès Gruart ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Mouse Models ◽

Temporal Lobe ◽

Neuronal Activity

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Reassessing the impact of intraoperative electrocorticography on postoperative outcome of patients undergoing standard temporal lobectomy for MRI-negative temporal lobe epilepsy

Journal of Neurosurgery ◽

10.3171/2018.11.jns182124 ◽

2020 ◽

Vol 132 (2) ◽

pp. 605-614 ◽

Cited By ~ 3

Author(s):

Sanjeet S. Grewal ◽

Mohammed Ali Alvi ◽

William J. Perkins ◽

Gregory D. Cascino ◽

Jeffrey W. Britton ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Univariate Analysis ◽

Temporal Lobectomy ◽

Seizure Outcome ◽

Incomplete Resection ◽

Seizure Recurrence ◽

Cox Regression Analysis ◽

Epileptiform Discharges ◽

The Impact

OBJECTIVEAlmost 30% of the patients with suspected temporal lobe epilepsy (TLE) have normal results on MRI. Success rates for resection of MRI-negative TLE are less favorable, ranging from 36% to 76%. Herein the authors describe the impact of intraoperative electrocorticography (ECoG) augmented by opioid activation and its effect on postoperative seizure outcome.METHODSAdult and pediatric patients with medically resistant MRI-negative TLE who underwent standardized ECoG at the time of their elective anterior temporal lobectomy (ATL) with amygdalohippocampectomy between 1990 and 2016 were included in this study. Seizure recurrence comprised the primary outcome of interest and was assessed using Kaplan-Meier and multivariable Cox regression analysis plots based on distribution of interictal epileptiform discharges (IEDs) recorded on scalp electroencephalography, baseline and opioid-induced IEDs on ECoG, and extent of resection.RESULTSOf the 1144 ATLs performed at the authors’ institution between 1990 and 2016, 127 (11.1%) patients (81 females) with MRI-negative TLE were eligible for this study. Patients with complete resection of tissue generating IED recorded on intraoperative ECoG were less likely to have seizure recurrence compared to those with incomplete resection on univariate analysis (p < 0.05). No difference was found in seizure recurrence between patients with bilateral independent IEDs and unilateral IEDs (p = 0.15), presence or absence of opioid-induced epileptiform activation (p = 0.61), or completeness of resection of tissue with opioid-induced IEDs on intraoperative ECoG (p = 0.41).CONCLUSIONSThe authors found that incomplete resection of IED-generating tissue on intraoperative ECoG was associated with an increased chance of seizure recurrence. However, they found that induction of epileptiform activity with intraoperative opioid activation did not provide useful intraoperative data predictive of improving operative results for temporal lobectomy in MRI-negative epilepsy.

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Adaptive Intrinsic Plasticity in Human Dentate Gyrus Granule Cells during Temporal Lobe Epilepsy

Cerebral Cortex ◽

10.1093/cercor/bhr294 ◽

2011 ◽

Vol 22 (9) ◽

pp. 2087-2101 ◽

Cited By ~ 27

Author(s):

M. Stegen ◽

F. Kirchheim ◽

A. Hanuschkin ◽

O. Staszewski ◽

R. W. Veh ◽

...

Keyword(s):

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Granule Cells ◽

Intrinsic Plasticity

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High similarity between EEG from subcutaneous and proximate scalp electrodes in patients with temporal lobe epilepsy

Journal of Neurophysiology ◽

10.1152/jn.00320.2018 ◽

2018 ◽

Vol 120 (3) ◽

pp. 1451-1460 ◽

Cited By ~ 13

Author(s):

Sigge Weisdorf ◽

Sirin W. Gangstad ◽

Jonas Duun-Henriksen ◽

Karina S. S. Mosholt ◽

Troels W. Kjær

Keyword(s):

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Temporal Dynamics ◽

Real Life ◽

High Similarity ◽

Time Frequency ◽

Scalp Eeg ◽

Eeg Recordings ◽

The Impact

Subcutaneous recording using electroencephalography (EEG) has the potential to enable ultra-long-term epilepsy monitoring in real-life conditions because it allows the patient increased mobility and discreteness. This study is the first to compare physiological and epileptiform EEG signals from subcutaneous and scalp EEG recordings in epilepsy patients. Four patients with probable or definite temporal lobe epilepsy were monitored with simultaneous scalp and subcutaneous EEG recordings. EEG recordings were compared by correlation and time-frequency analysis across an array of clinically relevant waveforms and patterns. We found high similarity between the subcutaneous EEG channels and nearby temporal scalp channels for most investigated electroencephalographic events. In particular, the temporal dynamics of one typical temporal lobe seizure in one patient were similar in scalp and subcutaneous recordings in regard to frequency distribution and morphology. Signal similarity is strongly related to the distance between the subcutaneous and scalp electrodes. On the basis of these limited data, we conclude that subcutaneous EEG recordings are very similar to scalp recordings in both time and time-frequency domains, if the distance between them is small. As many electroencephalographic events are local/regional, the positioning of the subcutaneous electrodes should be considered carefully to reflect the relevant clinical question. The impact of implantation depth of the subcutaneous electrode on recording quality should be investigated further. NEW & NOTEWORTHY This study is the first publication comparing the detection of clinically relevant, pathological EEG features from a subcutaneous recording system designed for out-patient ultra-long-term use to gold standard scalp EEG recordings. Our study shows that subcutaneous channels are very similar to comparable scalp channels, but also point out some issues yet to be resolved.

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