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Basic Science of Epilepsy

Adenosine kinase, glutamine synthetase and EAAT2 as gene therapy targets for temporal lobe epilepsy

For non-specialists

Young D, Fong DM, Lawlor PA, Wu A, Mouravlev A, McRae M, Glass M, Dragunow M, During MJ.
Gene Therapy, September 2014
Contributed by Sloka S. Iyengar, PhD

Objective – Anti-epileptic drugs (AEDs) manage seizures reasonably well, but they can be associated with refractoriness and side-effects. AEDs work via only a few known mechanisms, hence it is worthwhile putting in the effort to find additional targets for drug action. New drugs hold the promise of not only being more effective in stopping seizures, but also having fewer side effects. A novel target in the field of epilepsy is adenosine – a molecule that has anticonvulsant effects. The authors of a recent study investigated whether gene therapy targeting adenosine kinase (ADK) would be effective in an experimental model of seizures in rats. ADK is the enzyme that causes breakdown of adenosine; the thought being, blockade of the enzyme would allow more adenosine to be available for action

Results – The scientists first confirmed that the gene therapy approach did what it was meant to do – i.e. a substantial reduction in expression of ADK. Drugs used to simulate seizures in the lab are known as chemoconvulsants – one such drug is kainate. Using the gene therapy approach, the scientists found that rats with a reduction in ADK (and hence more adenosine) showed a reduction in seizures caused by kainate. Rats that experience kainate-induced seizures show a loss of neurons in a part of the hippocampus known as the hilus (as do people with epilepsy). Rats that had an increase in ADK showed that these neurons were protected.

Interpretation – This preclinical study has possible implications for discovery of newer AEDs. Gene therapy could be of special importance in a chronic disorder like epilepsy because of the potential to provide long-term beneficial effects with minimal side-effects. This study shows preliminary evidence that gene therapy targeting of adenosine may be beneficial in epilepsy.

Short summary for scientists – Anti-epileptic drugs (AEDs) work only via a few known targets; the authors of a recent study investigated whether astrocytes could prove to be a potential avenue for novel AED discovery. Adeno-associated viral (AAV) vector was used to overexpress glutamine synthetase (GS) and excitatory amino-acid transporter 2 (EAAT2) to increase synaptic glutamate clearance. Additionally, microRNA technique was used to decrease expression of the enzyme adenosine kinase (ADK), and increase synaptic levels of adenosine – a naturally occurring anticonvulsant. It was found that altering GS or EAAT2 did not affect seizures or neurodegeneration, but increasing adenosine levels did lead to a decrease in kainate-induced seizures and afforded neuroprotection.

Article


Tau reduction prevents disease in a mouse model of Dravet syndrome

Annals of Neurology

Ania L. Gheyara MD, PhD, Ravikumar Ponnusamy PhD, Biljana Djukic PhD, Ryan J. Craft BS, Kaitlyn Ho BS, Weikun Guo MS, Mariel M. Finucane PhD, Pascal E. Sanchez PhD, and Lennart Mucke MD
Annals of Neurology, Volume 76, Issue 3, pages 443-456, September 2014. Article first published online: 13 August 2014. DOI: 10.1002/ana.24230

Objective: Reducing levels of the microtubule-associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies.

Results: Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug-induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only 1 Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance.

Interpretation: Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies.

Abstract | Full Article | PDF


Workshop on Neurobiology of Epilepsy appraisal: New systemic imaging technologies to study the brain in experimental models of epilepsy

Epilepsia May 2014

Stefanie Dedeurwaerdere, Sandy R. Shultz, Paolo Federico, and Jerome Engel Jr
Epilepsia. doi: 10.1111/epi.12642; Article first published online: 16 May 2014

Successful application of functional neuroimaging of the whole brain in the animal laboratory now permits investigations during epileptogenesis and correlation with deep brain electroencephalography (EEG) activity. With the continuing development of these techniques and analytical methods, the potential for future translational research on epilepsy is enormous.

Abstract


Losartan prevents acquired epilepsy via TGF-β signaling suppression

Annals of Neurology

Guy Bar-Klein M.Med.Sc, Luisa P. Cacheaux Ph.D., Lyn Kamintsky M.Sc., Ofer Prager M.Med.Sc., Itai Weissberg M.Med.Sc., Karl Schoknecht M.D., Paul Cheng M.Sc., Soo Young Kim Ph.D., Lydia Wood Ph.D., Uwe Heinemann M.D., Ph.D., Daniela Kaufer Ph.D.2,, Alon Friedman M.D., Ph.D.
Annals of Neurology 2014, Accepted article. DOI: 10.1002/ana.24147

Objective: Acquired epilepsy is frequently associated with structural lesions following trauma, stroke and infections. While seizures are often difficult to treat, there is no clinically applicable strategy to prevent the development of epilepsy in patients at risk. We have recently shown that vascular injury is associated with activation of albumin-mediated transforming growth factor ß (TGF-ß) signaling, and followed by local inflammatory response and epileptiform activity ex vivo. Here we investigated albumin-mediated TGF-ß signaling and tested the efficacy of blocking the TGF-ß pathway in preventing epilepsy.

Abstract


Encapsulated galanin-producing cells attenuate focal epileptic seizures in the hippocampus

Epilepsia

Litsa Nikitidou, Malene Torp, Lone Fjord-Larsen, Philip Kusk, Lars U. Wahlberg, Mérab Kokaia
Epilepsia Article first published online: 18 November 2013
DOI: 10.1111/epi.12470

Our study shows that galanin-releasing encapsulated cell biodelivery (ECB) devices moderately suppress focal stimulation-induced recurrent seizures. Despite this moderate effect, the study provides conceptual proof that ECB could be a viable alternative approach to cell therapy in humans, with the advantage that the treatment could be terminated by removing these devices from the brain. Thereby, this strategy provides a higher level of safety for future therapeutic applications, in which genetically modified human cell lines that are optimized to produce and release antiepileptic compounds could be clinically evaluated for their seizure-suppressant effects.

Abstract | Full Article | PDF


Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism

Annals of Neurology

Yu Liu MD, PhD, Luis F. Lopez-Santiago PhD, Yukun Yuan PhD, Julie M. Jones MS, Helen Zhang MS, Heather A. O'Malley PhD, Gustavo A. Patino PhD, Janelle E. O'Brien PhD, Raffaella Rusconi PhD, Ajay Gupta MD, Robert C. Thompson PhD, Marvin R. Natowicz MD, PhD, Miriam H. Meisler PhD, Lori L. Isom PhD, Jack M. Parent MD

Annals of Neurology, Volume 74, Issue 1, pages 128-139, July 2013. Article first published online: 2 JUL 2013
doi : 10.1002/ana.23897

Objective: Neuronal channelopathies cause brain disorders, including epilepsy, migraine, and ataxia. Despite the development of mouse models, pathophysiological mechanisms for these disorders remain uncertain. One particularly devastating channelopathy is Dravet syndrome (DS), a severe childhood epilepsy typically caused by de novo dominant mutations in the SCN1A gene encoding the voltage-gated sodium channel Nav1.1. Heterologous expression of mutant channels suggests loss of function, raising the quandary of how loss of sodium channels underlying action potentials produces hyperexcitability. Mouse model studies suggest that decreased Nav1.1 function in interneurons causes disinhibition. We aim to determine how mutant SCN1A affects human neurons using the induced pluripotent stem cell (iPSC) method to generate patient-specific neurons.

Abstract | Article | PDF


GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior

Nature Neuroscience June 2013

Robert F Hunt, Kelly M Girskis, John L Rubenstein, Arturo Alvarez-Buylla, and Scott C Baraban
Nature Neuroscience 16, 692-697 (2013). Published online 05 May 2013
doi:10.1038/nn.3392

Impaired GABA-mediated neurotransmission has been implicated in many neurologic diseases, including epilepsy, intellectual disability and psychiatric disorders. We found that inhibitory neuron transplantation into the hippocampus of adult mice with confirmed epilepsy at the time of grafting markedly reduced the occurrence of electrographic seizures and restored behavioral deficits in spatial learning, hyperactivity and the aggressive response to handling.

Our results highlight a critical role for interneurons in epilepsy and suggest that interneuron cell transplantation is a powerful approach to halting seizures and rescuing accompanying deficits in severely epileptic mice.

Abstract


Basic research using animal models

Epilepsia - April 2013

The April 2013 issue of Epilepsia contains a number of basic research papers using animal models. The following two papers reflect the power and opportunity for applying "bench work" to the real problems of clinical epileptology.

Altered sleep regulation in a mouse model of SCN1A-derived Genetic Epilepsy with Febrile Seizures Plus (GEFS+)

Ligia A. Papale, Christopher D. Makinson, J. Christopher Ehlen, Sergio Tufik, Michael J. Decker, Ketema N. Paul, Andrew Escayg
Volume 54, Issue 4, pages.625-634, April 2013. Article first published online: 11 JAN 2013
DOI: 10.1111/epi.12060

Ethosuximide reduces epileptogenesis and behavioural comorbidity in the GAERS model of genetic generalised epilepsy

Gabi Dezsi, Ezgi Ozturk, Davor Stanic, Kim L. Powell, Hal Blumenfeld, Terence J. O'Brien, Nigel C. Jones
Volume 54, Issue 4, pages 635-643, April 2013. Article first published online: 6 March 2013
DOI: 10.1111/epi.12118


Canine epilepsy as a translational model?

Epilepsia Vol54 issue 3

Heidrun Potschka, Andrea Fischer, Eva-Lotta von Rüden, Velia Hülsmeyer, Wolfgang Baumgärtne
Epilepsia. Article first published online: 18 March 2013
doi: 10.1111/epi.12138

Dogs with spontaneous diseases can exhibit a striking similarity in etiology, clinical manifestation, and disease course when compared to human patients. Therefore, dogs are intensely discussed as a translational model of human disease. In particular, genetic studies in selected dog breeds serve as an excellent tool to identify epilepsy disease genes. The review gives an overview on the current state of knowledge regarding the etiology, clinical manifestation, pathology, and drug response of canine epilepsy, also pointing out the urgent need for further research on specific aspects. Moreover, the putative advantages, the disadvantages, and limitations of antiepileptic drug testing in canine epilepsy are critically discussed.

Abstract | Article | PDF


Detection of human papillomavirus in human focal cortical dysplasia type IIB

Annals of NeurologyChen J, Tsai V, Parker WE, Aronica E, Baybis M, Crino PB

Annals of Neurology Vol 72, Issue 6, pp. 881-892. December 2012. Article first published online: 31 Dec 2012. DOI: 10.1002/ana.23795

Objective: Focal cortical dysplasia type IIB (FCDIIB) is a sporadic developmental malformation of the cerebral cortex highly associated with pediatric epilepsy. Balloon cells (BCs) in FCDIIB exhibit constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. Recently, the high-risk human papillomavirus type 16 oncoprotein E6 was identified as a potent activator of mTORC1 signaling. Here, we test the hypothesis that HPV16 E6 is present in human FCDIIB specimens.

Interpretation: Our results indicate a new association between HPV16 E6 and FCDIIB and demonstrate for the first time HPV16 E6 in the human brain. We propose a novel etiology for FCDIIB based on HPV16 E6 expression during fetal brain development. ANN NEUROL 2012;72:881-892

Abstract | Article


Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects

Nature Medicine logoEva M Jimenez-Mateos, Tobias Engel, Paula Merino-Serrais, Ross C McKiernan, Katsuhiro Tanaka, Genshin Mouri, Takanori Sano, Colm O'Tuathaigh, John L Waddington, Suzanne Prenter, Norman Delanty, Michael A Farrell, Donncha F O'Brien, Ronán M Conroy, Raymond L Stallings, Javier DeFelipe, David C Henshall

Nature Medicine Volume:18, pages 1087-1094. 2012. doi:10.1038/nm.2834. Published online June 10, 2012

Abstract: Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation. Read article


New Edition: Jasper's Basic Mechanisms of Epilepsy

Cover image: Basic Mechanisms of Epilepsy

The editors of the historic textbook Jasper's Basic Mechanisms of Epilepsy announce the publication of the 4th edition by Oxford University Press. The book contains chapters from 90 international research groups summarizing the latest experimental advances in epilepsy for basic and clinical researchers.

This edition considers the role of interactions between neurons, synapses, and glia in the initiation, spread, and arrest of seizures. It examines mechanisms of excitability synchronization, and epileptogenesis and provides a framework for expanding the epilepsy genome and understanding complex heredity. It considers the mechanism of ion channelopathy, developmental epilepsy genes, and epilepsy comorbidities. And for the first time, it describes the current translation of epilepsy mechanisms into new therapeutic strategies.

Long considered the "bible" of basic epilepsy research, the volume provides encyclopedia coverage of current understanding and maps out new research directions for the coming decade.


Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE

Bianca Jupp, John Williams, David Binns, Rodney J. Hicks, Lisa Cardamone, Nigel Jones, Sandra Rees, Terence J. O'Brien
Epilepsia Article first published online: 12 JUN 2012. DOI: 10.1111/j.1528-1167.2012.03525.x

These findings demonstrate that hypometabolism occurs early in the processes of limbic epileptogenesis and is not merely a consequence of pyramidal cell loss or the progressive atrophy of limbic brain structures that follow. The hypometabolism may reflect cellular mechanisms occurring early during epileptogenesis in addition to any effects of the subsequent recurrent spontaneous seizures.

Abstract | Full Text | PDF


The origin of extracellular fields and currents – EEG, ECoG, LFP and spikes

György Buzsáki, Costas A. Anastassiou, & Christof Koch
Nature Reviews Neuroscience 13, 407-420 (June 2012) | doi:10.1038/nrn3241

Neuronal activity in the brain gives rise to transmembrane currents that can be measured in the extracellular medium. Although the major contributor of the extracellular signal is the synaptic transmembrane current, other sources – including Na+ and Ca2+ spikes, ionic fluxes through voltage – and ligand-gated channels, and intrinsic membrane oscillations – can substantially shape the extracellular field. High-density recordings of field activity in animals and subdural grid recordings in humans, combined with recently developed data processing tools and computational modelling, can provide insight into the cooperative behaviour of neurons, their average synaptic input and their spiking output, and can increase our understanding of how these processes contribute to the extracellular signal.

Abstract | Full Text | PDF


Hierarchical clustering of brain activity during human nonrapid eye movement sleep

Mélanie Boly, Vincent Perlbarg, Guillaume Marrelec, Manuel Schabus, Steven Laureys, Julien Doyon, Mélanie Pélégrini-Issac, Pierre Maquet, and Habib Benali
PNAS. Published online before print March 26, 2012, doi: 10.1073/pnas.1111133109.
PNAS April 10, 2012 vol. 109 no. 15 5856-5861

Consciousness is reduced during nonrapid eye movement (NREM) sleep due to changes in brain function that are still poorly understood. Here, we tested the hypothesis that impaired consciousness during NREM sleep is associated with an increased modularity of brain activity.

Abstract | PDF


Seizure-induced brain-born inflammation sustains seizure recurrence and blood-brain barrier damage

Laura Librizzi PhD, Francesco Noè PhD, Annamaria Vezzani PhD, Marco de Curtis MD1, Teresa Ravizza PhD
Annals of Neurology. Accepted manuscript online: 24 FEB 2012. DOI: 10.1002/ana.23567

Epilepsy is a common neurological disorder characterized by recurrent seizures often unresponsive to pharmacological treatment. Brain inflammation is considered a crucial etiopathogenetic mechanism of epilepsy that could be targeted to control seizures. Specific inflammatory mediators overexpressed in human epileptogenic foci are known to promote seizures in animal models. We investigate if seizures induce brain inflammation independently on extra-cerebral factors. We also verify whether brain-born inflammation is required and sufficient to maintain seizure activity and it supports blood-brain barrier (BBB) impairment. We addressed these questions by studying the relationship between seizures, inflammation and BBB permeability in a brain preparation isolated from extracerebral compartments.

Abstract | PDF


Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy

McClelland S, Flynn C, Dubé C, Richichi C, Zha Q, Ghestem A, Esclapez M, Bernard C, Baram TZ. (2011)
Annals of Neurology. 2011 Sep;70(3):454-64. doi: 10.1002/ana.22479.

Acquired HCN1 channelopathy derives from NRSF-mediated transcriptional repression that endures via chromatin modification and may provide insight into the mechanisms of a number of channelopathies that coexist with, and may contribute to, the conversion of a normal brain into an epileptic one.

Abstract | Full Text


Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy

Gilles Huberfeld, Liset Menendez de la Prida, Johan Pallud, Ivan Cohen, Michel Le Van Quyen, Claude Adam, Stephane Clemenceau, Michel Baulac and Richard Miles
Nature Neuroscience, May 2011 Volume 14, Issue 5, pp627 - 634, doi:10.1038/nn.2790

Brief and synchronous inter-ictal events can occur between seizures. Using human tissue samples and electroencephalography, this study shows that the transition from pre-ictal discharge to ictal discharge involves distinct temporal and spatial characteristics as well as glutamatergic mechanisms.

Abstract | Full Text | PDF


Single-neuron dynamics in human focal epilepsy

Wilson Truccolo, Jacob A Donoghue, Leigh R Hochberg, Emad N Eskandar, Joseph R Madsen, William S Anderson, Emery N Brown, Eric Halgren and Sydney S Cash
Nature Neuroscience, May 2011 Volume 14, Issue 5, pp635 - 641 doi:10.1038/nn.2782

Epileptic seizures are traditionally considered to reflect hypersynchronous neuronal activity arising from runaway excitation. Here the authors analyze spike train patterns of single neurons during seizures in human epilepsy patients, finding that spiking activity during seizure initiation was highly heterogeneous in small cortical patches and across the network.

Abstract | Full Text | PDF


A Novel Positron Emission Tomography Imaging Protocol Identifies Seizure-Induced Regional Overactivity of P-Glycoprotein at the Blood-Brain Barrier.

Bankstahl JP, Bankstahl M, Kuntner C, Stanek J, Wanek T, Meier M, Ding XQ, Müller M, Langer O, Löscher W.Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, and Center for Systems Neuroscience, 30559 Hannover, Germany, Health and Environment Department, Molecular Medicine, AIT Austrian Institute of Technology, 2444 Seibersdorf, Austria, Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria, and Department of Cardiology and Angiology and Institute of Diagnostic and Interventional Neuroradiology, Hannover Medical School, 30625 Hannover, Germany.
J Neuroscience 2011 Jun 15;31(24):8803-8811.

Read article


Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.

Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D, McPherson J, Bourquin T, Lewis L, Villasana D, Morgan M, Muzny D, Gibbs R, Noebels J.
Cell. 2011 Jun 24;145(7):1036-48.

Abstract | Full Text | PDF

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