scholarly journals An introduction to the mini‐symposium on “The Neuropathology of Focal Human Epilepsy”

2021 ◽  
Vol 31 (4) ◽  
Author(s):  
Ingmar Blümcke
Keyword(s):  
Human Epilepsy

scholarly journals An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Janire Urrutia ◽  
Alejandra Aguado ◽  
Carolina Gomis-Perez ◽  
Arantza Muguruza-Montero ◽  
Oscar R. Ballesteros ◽  
...  
Keyword(s):  
Structural Instability ◽  
Binding Assays ◽  
Iq Motif ◽  
Channel Function ◽  
Human Epilepsy ◽  
Pathogenic Variants ◽  
In Silico Studies ◽  
Nascent Chain

Abstract Background The amino acid sequence of proteins generally carries all the necessary information for acquisition of native conformations, but the vectorial nature of translation can additionally determine the folding outcome. Such consideration is particularly relevant in human diseases associated to inherited mutations leading to structural instability, aggregation, and degradation. Mutations in the KCNQ2 gene associated with human epilepsy have been suggested to cause misfolding of the encoded Kv7.2 channel. Although the effect on folding of mutations in some domains has been studied, little is known of the way pathogenic variants located in the calcium responsive domain (CRD) affect folding. Here, we explore how a Kv7.2 mutation (W344R) located in helix A of the CRD and associated with hereditary epilepsy interferes with channel function. Results We report that the epilepsy W344R mutation within the IQ motif of CRD decreases channel function, but contrary to other mutations at this site, it does not impair the interaction with Calmodulin (CaM) in vitro, as monitored by multiple in vitro binding assays. We find negligible impact of the mutation on the structure of the complex by molecular dynamic computations. In silico studies revealed two orientations of the side chain, which are differentially populated by WT and W344R variants. Binding to CaM is impaired when the mutated protein is produced in cellulo but not in vitro, suggesting that this mutation impedes proper folding during translation within the cell by forcing the nascent chain to follow a folding route that leads to a non-native configuration, and thereby generating non-functional ion channels that fail to traffic to proper neuronal compartments. Conclusions Our data suggest that the key pathogenic mechanism of Kv7.2 W344R mutation involves the failure to adopt a configuration that can be recognized by CaM in vivo but not in vitro.

scholarly journals Dissecting the Molecular Determinants of GABAA Receptors Current Rundown, a Hallmark of Refractory Human Epilepsy

2021 ◽  
Vol 11 (4) ◽  
pp. 441
Author(s):  
Pierangelo Cifelli ◽  
Silvia Di Angelantonio ◽  
Veronica Alfano ◽  
Alessandra Morano ◽  
Eleonora De Felice ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Drug Resistant ◽  
Human Embryonic Kidney Cells ◽  
Inhibitory Function ◽  
Human Epilepsy ◽  
Wide Range ◽  
Molecular Determinants ◽  
The Central Nervous System ◽  
Heterologous Expression Systems ◽  
Important Therapeutic Target

GABAA receptors-(Rs) are fundamental for the maintenance of an efficient inhibitory function in the central nervous system (CNS). Their dysfunction is associated with a wide range of CNS disorders, many of which characterized by seizures and epilepsy. Recently, an increased use-dependent desensitization due to a repetitive GABA stimulation (GABAA current rundown) of GABAARs has been associated with drug-resistant temporal lobe epilepsy (TLE). Here, we aimed to investigate the molecular determinants of GABAA current rundown with two different heterologous expression systems (Xenopus oocytes and human embryonic kidney cells; HEK) which allowed us to manipulate receptor stoichiometry and to study the GABAA current rundown on different GABAAR configurations. To this purpose, we performed electrophysiology experiments using two-electrode voltage clamp in oocytes and confirming part of our results in HEK. We found that different degrees of GABAA current rundown can be associated with the expression of different GABAAR β-subunits reaching the maximum current decrease when functional α1β2 receptors are expressed. Furthermore, the blockade of phosphatases can prevent the current rundown observed in α1β2 GABAARs. Since GABAAR represents one important therapeutic target in the treatment of human epilepsy, our results could open new perspectives on the therapeutic management of drug-resistant patients showing a GABAergic impairment.

scholarly journals Microscale dynamics of electrophysiological markers of epilepsy

2020 ◽  
Author(s):  
Jimmy C. Yang ◽  
Angelique C. Paulk ◽  
Sang Heon Lee ◽  
Mehran Ganji ◽  
Daniel J. Soper ◽  
...  
Keyword(s):  
Spatial Resolution ◽  
High Frequency ◽  
Time Windows ◽  
List Type ◽  
Spatiotemporal Resolution ◽  
Similar Time ◽  
Human Epilepsy ◽  
High Frequency Oscillations ◽  
Peak Tracking ◽  
Interictal Discharges

AbstractObjectiveInterictal discharges (IIDs) and high frequency oscillations (HFOs) are neurophysiologic biomarkers of epilepsy. In this study, we use custom poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) microelectrodes to better understand their microscale dynamics.MethodsElectrodes with spatial resolution down to 50µm were used to record intraoperatively in 30 subjects. For IIDs, putative spatiotemporal paths were generated by peak-tracking, followed by clustering. For HFOs, repeating patterns were elucidated by clustering similar time windows. Fast events, consistent with multi-unit activity (MUA), were covaried with either IIDs or HFOs.ResultsIIDs seen across the entire array were detected in 93% of subjects. Local IIDs, observed across <50% of the array, were seen in 53% of subjects. IIDs appeared to travel across the array in specific paths, and HFOs appeared in similar repeated spatial patterns. Finally, microseizure events were identified spanning 50-100µm. HFOs covaried with MUA, but not with IIDs.ConclusionsOverall, these data suggest micro-domains of irritable cortex that form part of an underlying pathologic architecture that contributes to the seizure network.SignificanceMicroelectrodes in cases of human epilepsy can reveal dynamics that are not seen by conventional electrocorticography and point to new possibilities for their use in the diagnosis and treatment of epilepsy.HighlightsPEDOT:PSS microelectrodes with at least 50µm spatial resolution uniquely reveal spatiotemporal patterns of markers of epilepsyHigh spatiotemporal resolution allows interictal discharges to be tracked and reveal cortical domains involved in microseizuresHigh frequency oscillations detected by microelectrodes demonstrate localized clustering on the cortical surface

Brain sodium MRI in human epilepsy: Disturbances of ionic homeostasis reflect the organization of pathological regions

NeuroImage ◽  
2017 ◽  
Vol 157 ◽  
pp. 173-183 ◽  
Author(s):  
Ben Ridley ◽  
Angela Marchi ◽  
Jonathan Wirsich ◽  
Elisabeth Soulier ◽  
Sylviane Confort-Gouny ◽  
...  
Keyword(s):  
Ionic Homeostasis ◽  
Sodium Mri ◽  
Human Epilepsy

scholarly journals Focal Increases in Perfusion and Decreases in Hemoglobin Oxygenation Precede Seizure Onset in Spontaneous Human Epilepsy

Epilepsia ◽  
2007 ◽  
Vol 48 (11) ◽  
pp. 2059-2067 ◽  
Author(s):  
Mingrui Zhao ◽  
Minah Suh ◽  
Hongtao Ma ◽  
Challon Perry ◽  
Andrew Geneslaw ◽  
...  
Keyword(s):  
Seizure Onset ◽  
Human Epilepsy ◽  
Hemoglobin Oxygenation

Theta power and theta-gamma coupling support spatial memory retrieval

2019 ◽  
Author(s):  
Umesh Vivekananda ◽  
Daniel Bush ◽  
James A Bisby ◽  
Sallie Baxendale ◽  
Roman Rodionov ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Task Performance ◽  
Memory Function ◽  
Memory Task ◽  
Theta Oscillations ◽  
Theta Power ◽  
Human Epilepsy ◽  
Phase Amplitude ◽  
Hippocampal Theta

AbstractHippocampal theta oscillations have been implicated in spatial memory function in both rodents and humans. What is less clear is how hippocampal theta interacts with higher frequency oscillations during spatial memory function, and how this relates to subsequent behaviour. Here we asked ten human epilepsy patients undergoing intracranial EEG recording to perform a desk-top virtual reality spatial memory task, and found that increased theta power in two discrete bands (‘low’ 2-5Hz and ‘high’ 6-9Hz) during cued retrieval was associated with improved task performance. Similarly, increased coupling between ‘low’ theta phase and gamma amplitude during the same period was associated with improved task performance. These results support a role of theta oscillations and theta-gamma phase-amplitude coupling in human spatial memory function.

Dogs as predictors of human epilepsy

1991 ◽  
Vol 129 (11) ◽  
pp. 251-251 ◽  
Author(s):  
A. Edney
Keyword(s):  
Human Epilepsy
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