EPITARGET NEWS | Issue 5 | 03/2017
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EPITARGET NEWS | Issue 5 | 03/2017

Welcome to the fifth EPITARGET newsletter!

In the 5th issue of the EPITARGET newsletter, we would like to update you about the latest EPITARGET meeting, EPITARGET publications, recent oral and poster presentations as well as the International Epilepsy Day.


Recent EPITARGET events

4th General Assembly Meeting in Marseille 26-28 October 2016

The EPITARGET Consortium met in October 2016 in Marseille. The meeting was hosted by EPITARGET partner Aix Marseille Université. At the meeting all partners updated each other on the work done since the last meeting and discussed the next steps and potential challenges.

The meeting was preceded by the 2nd EPITARGET Young Researchers’ Symposium during which the young investigators of EPITARGET got the chance to present their work in presentations as well as posters. Two young researchers - James Mills (AMC) and Natascha Surano (UBMC) - were awarded with certificates for the best oral presentation and the best poster by a committee of experts within the consortium nominated by the coordinator, Mérab Kokaia.

EPITARGET Consortium in Marseille

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Epilepsy Awareness

International Epilepsy Day 2017

On 13th February was the 3rd International Epilepsy Day which has the purpose to raise awareness for epilepsy and the struggles with which affected patients and families are confronted. The theme for this year’s International Epilepsy Day was: Putting Epilepsy in the Picture.

The researchers from the EPITARGET coordinator Lund University joined forces with the Swedish epilepsy patient organization on that day to raise awareness for Epilepsy and to highlight current research performed at Lund University on new treatments for the disease. For this purpose an event was organised for the public in the City Library in downtown Lund with discussions and seminars on epilepsy.

International Epilepsy Day in Lund

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EPITARGET publications

Recent EPITARGET Publications sorted by PubMed ID

Ravizza T, Onat FY, Brooks-Kayal AR, Depaulis A, Galanopoulou AS, Mazarati A, Numis AL, Sankar R, Friedman A. WONOEP appraisal: Biomarkers of epilepsy-associated comorbidities. Epilepsia. 2016 Dec 30.

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting. We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as JAK/STAT, mTOR and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, inflammatory cytokines, and genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities.

Iori V, Iyer AM, Ravizza T, Beltrame L, Paracchini L, Marchini S, Cerovic M, Hill C, Ferrari M, Zucchetti M, Molteni M, Rossetti C, Brambilla R, Steve White H, D'Incalci M, Aronica E, Vezzani A. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis, 2016, 99: 12-23.

We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci, it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy.

van Vliet EA, Dedeurwaerdere S, Cole AJ, Friedman A, Koepp MJ, Potschka H, Immonen R, Pitkänen A, Federico P. WONOEP appraisal: imaging biomarkers in epilepsy. Epilepsia. 2016 Nov 24.

Neuroimaging offers a wide range of opportunities to obtain information about neuronal activity, brain inflammation, blood-brain barrier alterations, and various molecular alterations during epileptogenesis or for the prediction of pharmacoresponsiveness as well as postoperative outcome. Imaging biomarkers were examined during the XIII Workshop on Neurobiology of Epilepsy (XIII WONOEP) organized in 2015 by the Neurobiology Commission of the International League Against Epilepsy (ILAE). Here we present an extended summary of the discussed issues and provide an overview of the current state of knowledge regarding the biomarker potential of different neuroimaging approaches for epilepsy.

Liu JY, Reeves C, Diehl B, Coppola A, Al-Hajri A, Hoskote C, Mughairy SA, Tachrount M, Groves M, Michalak Z, Mills K, McEvoy AW, Miserocchi A, Sisodiya SM, Thom M. Early lipofuscin accumulation in frontal lobe epilepsy. Ann Neurol. 2016 Dec;80(6):882-895.

This study reports on novel brain pathology in young patients with frontal lobe epilepsy (FLE) that is distinct from focal cortical dysplasia (FCD). We examined surgical tissue from 20 young patients with FLE (mean age, 30 years) : 6 patients with Frontal lobe epilepsy with Neuronal Lipofuscin (FNL), 7 frontal lobe epilepsy-pathology negative (pathology-negative) and 7 Focal Cortical Dysplasia IIB (FCD IIB). We observed excessive lipofuscin accumulation in abnormal dysmorphic neurones in all FNL cases, but not in FCD type IIB and pathology-negative cases. These abnormal dysmorphic neurones on proteomics analysis were comparable to aged human brains. The mTOR pathway was activated, as in cases with dysplasia, but the immunoreactivities of nucleoporin p62, DEP-domain containing protein 5, clathrin, and dynamin-1 were different between groups, suggesting that enhanced autophagy flux and abnormal synaptic vesicle trafficking contribute to early lipofuscin aggregation in these cases, compared to suppression of autophagy in cases with typical dysplasia. Cases with abnormal neuronal lipofuscin showed subtle magnetic resonance imaging cortical abnormalities that localized with seizure onset zone and were more likely to have a family history. We propose that excess neuronal lipofuscin accumulation in young patients with FLE represents a novel pathology underlying this epilepsy; the early accumulation of lipofuscin may be disease driven, secondary to as-yet unidentified drivers accelerating autophagic pathways, which may underpin the neuronal dysfunction in this condition.

Bar-Klein G, Klee R, Brandt C, Bankstahl M, Bascuñana P, Töllner K, Dalipaj H, Bankstahl JP, Friedman A, Löscher W. Isoflurane prevents acquired epilepsy in rat models of temporal lobe epilepsy. Ann Neurol. 2016 Dec;80(6):896-908.

Acquired epilepsy is a devastating long-term risk of various brain insults, including trauma, stroke, infections, and status epilepticus (SE). There is no preventive treatment for patients at risk. Due to the complex alterations involved in epileptogenesis, it is likely that multi-targeted approaches are required for epilepsy prevention. We report novel preclinical findings with isoflurane, which exerts various non-anesthetic effects that may be relevant for anti-epileptogenesis.

The effects of isoflurane were investigated in two rat models of SE induced epilepsy: intrahippocampal kainate and systemic administration of paraoxon. Isoflurane was either administered during (kainate) or after (paraoxon) induction of SE. Magnetic resonance imaging was used to assess blood-brain barrier dysfunction. Positron emission tomography was used to visualize neuroinflammation. Long-term electrocorticographic recordings were used to monitor spontaneous recurrent seizures. Neuronal damage was assessed histologically.

In the absence of isoflurane, spontaneous recurrent seizures were common in the majority of rats in both models. When isoflurane was administered during kainate injection, the duration and severity of SE were not affected, but only few rats developed spontaneous recurrent seizures. A similar anti-epileptogenic effect was found when paraoxon-treated rats were exposed to isoflurane after SE. Moreover, in the latter model, isoflurane prevented blood-brain barrier dysfunction and neurodegeneration, whereas isoflurane reduced neuroinflammation in the kainate model.

Since isoflurane is a widely used volatile anesthetic, and is used for inhalational long-term sedation in critically ill patients at risk to develop epilepsy, our findings hold a promising potential to be successfully translated into the clinic.

van Scheppingen J, Broekaart DW, Scholl T, Zuidberg MR, Anink JJ, Spliet WG, van Rijen PC, Czech T, Hainfellner JA, Feucht M, Mühlebner A, van Vliet EA, Aronica E. Dysregulation of the (immuno)proteasome pathway in malformations of cortical development. J Neuroinflammation. 2016 Aug 26;13(1):202.

The proteasome is a multisubunit enzyme complex involved in protein degradation, which is essential for many cellular processes. During inflammation, the constitutive subunits are replaced by their inducible counterparts, resulting in the formation of the immunoproteasome. In this study we showed increased expression of (immuno)proteasome subunits in malformations of cortical development: focal cortical dysplasia (FCD) IIa and b, cortical tubers from patients with tuberous sclerosis complex (TSC), and in mild malformations of cortical development. Expression of both constitutive and immunoproteasome subunits in FCD II-derived astroglial cultures was negatively regulated by treatment with the immunomodulatory drug rapamycin (inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is activated in both TSC and FCD II). These observations support the dysregulation of the proteasome system in both FCD and TSC and provide new insights on the mechanism of regulating the (immuno)proteasome in astrocytes and the molecular links between inflammation, mTOR activation, and epilepsy.

Jonsson A, Inal S, Uguz L, Williamson AJ, Kergoat L, Rivnay J, Khodagholy D, Berggren M, Bernard C, Malliaras GG, Simon DT. Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site. Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9440-5.

In this work, we demonstrate an organic electronic device that can, at the same site, both measure the electrical activity of the brain and deliver molecules (like medical drugs) directly to neurones. The device is non-invasive (10 times thinner than hair) and biocompatible. This device opens the way to autonomous systems that could deliver drugs when and where they are needed.

Löscher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res. 2016 Oct;126:157-84.

Animal seizure and epilepsy models continue to play an important role in the early discovery of new therapies for the symptomatic treatment of epilepsy.  However, several unmet clinical needs remain, including resistance to ASDs (anti-seizure drugs) in about 30% of patients with epilepsy, adverse effects of ASDs that can reduce quality of life, and the lack of treatments that can prevent development of epilepsy in patients at risk following brain injury. The aim of this review is to critically discuss the translational value of currently used animal models of seizures and epilepsy, particularly what animal models can tell us about epilepsy therapies in patients and which limitations exist. Principles of translational medicine, including the fit-for-purpose paradigm, will be used for this discussion.

Tai XY, Koepp M, Duncan JS, Fox N, Thompson P, Baxendale S, Liu JY, Reeves C, Michalak Z, Thom M. Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections. Brain. 2016 Sep;139(Pt 9):2441-55.

Temporal lobe epilepsy is associated with a high prevalence of cognitive impairment. Tau, the microtubule-associated protein, is a hallmark of several neurodegenerative diseases including Alzheimer’s disease and chronic traumatic encephalopathy. We hypothesized that hyperphosphorylated tau pathology is associated with cognitive decline in temporal lobe epilepsy. We examined tissue from 33 patients who had undergone temporal lobe resection between ages 50 and 65 years.  Hyperphosphorylated tau pathology was present in 94% of cases and 12 % had a Braak staging III-IV. We identified a mixture of tau pathology patterns characteristic of Alzheimer’s disease and chronic traumatic encephalopathy. Moreover, unusual patterns of subpial tau deposition, sparing of the hippocampus and co-localization with mossy fibre sprouting was observed. We demonstrated that the more extensive the tau pathology, the greater the decline in verbal learning, recall and graded naming test scores over 1-year post-temporal lobe resection. We found an association between modified tau score and history of secondary generalized seizures. Our findings suggest an epilepsy-related tauopathy in temporal lobe epilepsy, which contributes to accelerated cognitive decline and has diagnostic and treatment implications.

Rizzi M, Weissberg I, Milikovsky DZ, Friedman A. Following a potential epileptogenic insult, prolonged high rates of nonlinear dynamical regimes of intermittency type is the hallmark of epileptogenesis. Sci Rep. 2016, 4;6:31129.

The lack of a marker of epileptogenesis is an unmet medical need, not only from the clinical perspective but also from the point of view of the pre-clinical research. Indeed, the lack of this kind of marker affects the investigations on the mechanisms of epileptogenesis as well as the development of novel therapeutic approaches aimed to prevent or to mitigate the severity of the incoming epilepsy in humans. In this work, we provide evidence that in an experimental model of epileptogenesis that mimics the alteration of the blood-brain barrier permeability, a key-mechanism that contributes to the development of epilepsy in humans and in animals, the prolonged occurrence in the electrocorticograms (ECoG) of high rates of a nonlinear dynamical regimes known as intermittency univocally characterizes the population of experimental animals which develop epilepsy, hence it can be considered as the first biophysical marker of epileptogenesis.

Vazana U, Veksler R, Pell GS, Prager O, Fassler M, Chassidim Y, Roth Y, Shahar H, Zangen A, Raccah R, Onesti E, Ceccanti M, Colonnese C, Santoro A, Salvati M, D'Elia A, Nucciarelli V, Inghilleri M, Friedman A. Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery. J Neurosci. 2016 Jul 20;36(29):7727-39.

The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability. We show that recurrent seizures and the associated excessive release of the neurotransmitter glutamate lead to increased vascular permeability through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.

Breuer H, Meier M, Schneefeld S, Härtig W, Wittneben A, Märkel M, Ross TL, Bengel FM, Bankstahl M, Bankstahl JP. Multimodality imaging of blood-brain barrier impairment during epileptogenesis. J Cereb Blood Flow Metab. 2016 Jul 19.

Insult-associated blood–brain barrier leakage is strongly suggested to be a key step during epileptogenesis. In this study, we used three non-invasive translational imaging modalities, i.e. positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging, to evaluate BBB leakage after an epileptogenic brain insult.
Sprague-Dawley rats were scanned during early epileptogenesis initiated by status epilepticus. Positron emission tomography and single photon emission computed tomography scans were performed using the novel tracer [68Ga]DTPA or [99mTc]DTPA, respectively. Magnetic resonance imaging included T2 and post-contrast T1 sequence after infusion of Gd-DTPA, gadobutrol, or Gd-albumin.

All modalities revealed increased blood–brain barrier permeability 48 h post status epilepticus, mainly in epileptogenesis-associated brain regions like hippocampus, piriform cortex, thalamus, or amygdala. In hippocampus, Gd-DTPA-enhanced T1 magnetic resonance imaging signal was increased by 199%, [68Ga]DTPA positron emission tomography by 37%, and [99mTc]DTPA single photon emission computed tomography by 56%. Imaging results were substantiated by histological detection of albumin extravasation.

Comparison with quantitative positron emission tomography and single photon emission computed tomography shows that magnetic resonance imaging sequences successfully amplify the signal from a moderate amount of extravasated DTPA molecules, enabling sensitive detection of blood–brain barrier disturbance in epileptogenesis. Imaging of the disturbed blood–brain barrier will give further pathophysiologic insights, will help to stratify anti-epileptogenic treatment targeting blood–brain barrier integrity, and may serve as a prognostic biomarker.

Robens BK, Grote A, Pitsch J, Schoch S, Cardoso C, Becker AJ. Minute amounts of hamartin wildtype rescue the emergence of tuber-like lesions in conditional Tsc1 ablated mice. Neurobiol Dis. 2016 Nov;95:134-44.

Focal epilepsy manifests often in tubers of patients with tuberous sclerosis (TSC) which is a phacomatosis associated with highly differentiated malformations including those in the brain. The authors have tested the morphological and structural effects of mutated TSC1 variants by intraventricular in utero electroporation (IUE), genetically mimicking the discrete focal character and a somatic postzygotic mosaicism of the lesion, focusing on the gene dosage required for tuber-like lesions to emerge in Tsc1(flox/flox) mice. These studies revealed that already minimal amounts of functional hamartin are sufficient for phenotype rescue. Analyzing the dosage of aberrant molecule variants may represent important future biomarkers to develop gene therapy strategies further.

Ahl M, Avdic U, Skoug C, Ali I, Chugh D, Johansson UE, Ekdahl CT. Immune response in the eye following epileptic seizures. J Neuroinflammation. 2016 Jun 27;13(1):155.

Temporal lobe seizures in rats lead to inflammation in the eyes. Electrically-induced partial status epilepticus (SE) originating from the right temporal lobe in rats were found to induce micro- and macroglia activation in the retina of both the right and left eye 7 weeks later. These changes were not visible within the first week following SE. Immune modulating therapy by intracerebroventricular infusion of the chemokine receptor antibody, CX3CR1 Ab, alleviated both micro- and macroglial activation.

Brandt C, Bankstahl M, Töllner K, Klee R, Löscher W. The pilocarpine model of temporal lobe epilepsy: Marked intrastrain differences in female Sprague-Dawley rats and the effect of estrous cycle. Epilepsy Behav. 2016 Aug;61:141-52.

Rat strains such as Sprague-Dawley (SD) or Wistar are widely used in epilepsy research, including popular models of temporal lobe epilepsy in which spontaneous recurrent seizures (SRS), hippocampal damage, and behavioral alterations develop after status epilepticus (SE). Such rats are randomly outbred, and outbred strains are known to be genetically heterogeneous populations with a high intrastrain variation. Intrastrain differences may be an important reason for discrepancies between studies from different laboratories, but the extent to which such differences affect development of seizures, neurodegeneration, and psychopathology in post-SE models of epilepsy has received relatively little attention. In the present study, we induced SE by systemic administration of pilocarpine in SD and Wistar rats from different breeders. Marked intrastrain differences in induction of SE and its long-term consequences were found, whereas susceptibility to pilocarpine was hardly affected by the estrous cycle. The marked intrastrain differences provide an interesting tool to study the impact of genetic and environmental factors on seizure susceptibility, epileptogenesis, and the relationship between behavior and epilepsy and vice versa.

Brandt C, Rankovic V, Töllner K, Klee R, Bröer S, Löscher W. Refinement of a model of acquired epilepsy for identification and validation of biomarkers of epileptogenesis in rats. Epilepsy Behav. 2016 Aug;61:120-31.

In rodent models in which a status epilepticus (SE) is used to induce epilepsy, typically most animals develop spontaneous recurrent seizures (SRS). A high incidence of epilepsy is an advantage in the search of antiepileptogenic treatments, whereas it is a disadvantage in the search for biomarkers of epileptogenesis, because it does not allow comparing potential biomarkers in animals that either develop or do not develop epilepsy. The aim of this project was refinement of an established SE rat model, so that only ~50% of the animals develop epilepsy. For this purpose, we used an electrical model of SE induction, in which a self-sustained SE develops after prolonged stimulation of the basolateral amygdala. When SE duration was restricted to 2.5 h by diazepam, this resulted in epilepsy development in only 50% of rats, thus reaching the goal of the project. The latent period to onset of SRS was >2 weeks in most rats. Development of epilepsy could be predicted in most rats by behavioral hyperexcitability. The refined SE model may offer a platform to identify and validate biomarkers of epileptogenesis.

Pitkänen A, Löscher W, Vezzani A, Becker AJ, Simonato M, Lukasiuk K, Gröhn O, Bankstahl JP, Friedman A, Aronica E, Gorter JA, Ravizza T, Sisodiya SM, Kokaia M, Beck H. Advances in the development of biomarkers for epilepsy. Lancet Neurol. 2016 Jul;15(8):843-56.

Over 50 million people worldwide have epilepsy. In nearly 30% of these cases, epilepsy remains unsatisfactorily controlled despite the availability of over 20 antiepileptic drugs. Moreover, no treatments exist to prevent the development of epilepsy in those at risk, despite an increasing understanding of the underlying molecular and cellular pathways.

The vision of developing targeted treatments for epilepsy relies upon the development of biomarkers that allow individually tailored treatment. EPITARGET consortium reviewed the current status of biomarker development for epilepsy in recent Lancet Neurology article. Biomarkers typically fall into two broad categories: diagnostic biomarkers, which provide information on the clinical status of, and potentially the sensitivity to specific treatments, and prognostic biomarkers, which allow prediction of future clinical features, such as the speed of progression, severity of epilepsy, development of comorbidities, or prediction of remission or cure.

As discussed, research in plasma microRNAs and magnetic resonance imaging have already suggested diagnostic biomarker for diagnosis of epilepsy and drug-refractoriness. However, the research faces several challenges. One challenge, as pinpointed by Dr. Koepp in his commentary is “to define the timepoint during epileptogenesis after which it is too late to prevent the first seizure”.

Commentary: Koepp MJ. The help of biomarkers in the prevention of epilepsy. Lancet Neurol. 2016 Jul;15(8):782-4. doi: 10.1016/S1474-4422(16)30081-3. PubMed PMID: 27302346.

Bernard C. The Diathesis-Epilepsy Model: How Past Events Impact the Development of Epilepsy and Comorbidities. Cold Spring Harb Perspect Med. 2016 Jun 1;6(6).

In this work, I introduce the diathesis-epilepsy model. Diathesis is the intrinsic vulnerability of an individual, which depends on one’s genetic background and life experiences. The model posits that some past events (like intense stress) can leave a mark in the brain of individuals making them more susceptible to develop epilepsy and co-morbidities, including depression and cognitive deficits. I describe several results showing that vulnerability can be detected and reversed.

Pabst M, Braganza O, Dannenberg H, Hu W, Pothmann L, Rosen J, Mody I, van Loo K, Deisseroth K, Becker AJ, Schoch S, Beck H. Astrocyte Intermediaries of Septal Cholinergic Modulation in the Hippocampus. Neuron. 2016 May 18;90(4):853-65.

The neurotransmitter acetylcholine, derived from the medial septum/diagonal band of Broca complex, was suggested to have an important role in hippocampal learning and memory processes. In this publication the authors demonstrate that acetylcholine release from cholinergic septohippocampal projections causes a long-lasting GABAergic inhibition of hippocampal dentate granule cells in vivo and in vitro. The data further suggest that acetylcholine release can cause slow inhibition of principal neuronal activity by astrocyte intermediaries. Alterations of this delicate cellular interplay can be of major importance in the emergence of hyperexcitability during epileptogenesis.

Brackhan M, Bascuñana P, Postema JM, Ross TL, Bengel FM, Bankstahl M, Bankstahl JP. Serial Quantitative TSPO-Targeted PET Reveals Peak Microglial Activation up to 2 Weeks After an Epileptogenic Brain Insult. J Nucl Med. 2016 Aug;57(8):1302-8.

Experimental and clinical evidence suggests that neuroinflammation, triggered by epileptogenic insults, contributes to seizure development. We employed translocator protein (TSPO)-targeted molecular imaging to obtain further insights into the role of microglial activation during epileptogenesis.

As epileptogenic insult, a status epilepticus (SE) was induced in rats by lithium-pilocarpine. Rats were subjected to 11C-PK11195 positron emission tomography (PET) scans before SE, immediately after SE, at 1, 2, 5, 7, 14, and 22 days, and 14-16 weeks post SE. For data evaluation, brain regions were outlined by co-registration with a standard rat brain atlas, and % injected dose/cc and binding potential (simplified reference tissue model with cerebellar gray matter as reference region) were calculated. For autoradiography and immunohistochemical evaluation, additional rats were decapitated without prior SE or 2, 5 or 14 days post SE.

Following SE, increases in 11C-PK11195 uptake and binding potential were evident in epileptogenesis-associated brain regions, such as hippocampus, thalamus or piriform cortex, but not in the cerebellum beginning at 2-5 days and persisting at least 3 weeks after SE. Maximal regional signal was observed at 1-2 weeks after SE. Autoradiography confirmed the spatiotemporal profile. Immunohistochemical evaluation revealed microglial and astroglial activation as well as neuronal cell loss in epileptogenesis-associated brain regions at all investigated time points. The time course of microglial activation was consistent with that demonstrated by tracer techniques.

TSPO-targeted PET is a reliable tool for identifying brain inflammation during epileptogenesis. Neuroinflammation mainly affects brain regions commonly associated with seizure generation and spread. Definition of the time profile of neuroinflammation may facilitate the development of inflammation-targeted, anti-epileptogenic therapy.

Volmering E, Niehusmann P, Peeva V, Grote A, Zsurka G, Altmüller J, Nürnberg P, Becker AJ, Schoch S, Elger CE, Kunz WS. Neuropathological signs of inflammation correlate with mitochondrial DNA deletions in mesial temporal lobe epilepsy. Acta Neuropathol. 2016 Aug;132(2):277-88.

Accumulation of mitochondrial DNA deletions was linked to the presence of respiratory-deficient neurons in several CNS diseases. This study demonstrates a coincidence of hippocampal sclerosis, the increased presence of a specific mitochondrial DNA deletion and extensive inflammatory infiltrates and thereby supports the hypothesis that chronic inflammation leads to mitochondrial dysfunction by reactive oxygen species-mediated mitochondrial DNA mutagenesis, which promotes epileptogenesis. Improving biomarkers for inflammation during epileptogenesis will be helpful to develop strategies against this neurotoxic mechanism.

Salar S, Lapilover E, Müller J, Hollnagel JO, Lippmann K, Friedman A, Heinemann U. Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin. Neurobiol Dis. 2016 Jul;91:155-65.

Epileptogenesis following insults to the brain may be triggered by a dysfunctional blood-brain barrier (BBB) associated with albumin extravasation, activation of astrocytes and impaired control of extracellular potassium and glutamate. We hypothesized that the BBB-deprived hippocampus involves alterations in synaptic interactions. We therefore assessed the effects of intracerebral application of serum albumin (imitating BBB breakdown) on homo- and heterosynaptic plasticity in hippocampal CA1. We found alterations in both homo- and heterosynaptic plasticity compared to control conditions in ex vivo slice studies. Albumin-treated tissue reveals (1) reduced long-term depression following low-frequency stimulation; (2) increased long-term potentiation of population spikes in response to 20Hz stimulation; (3) potentiated responses to Schaffer collateral stimulation following high-frequency stimulation of the direct cortical input and low-frequency stimulation of alveus and finally, (4) TGFβ receptor II (TGFβR-II) involvement in albumin-induced homosynaptic plasticity changes. We conclude that albumin-induced epileptogenesis and network hyperexcitability is associated with abnormal homo- and heterosynaptic plasticity that could partly be reversed by interference with TGFβR-II-mediated signaling.

Bungenberg J, Surano N, Grote A, Surges R, Pernhorst K, Hofmann A, Schoch S, Helmstaedter C, Becker AJ. Gene expression variance in hippocampal tissue of temporal lobe epilepsy patients corresponds to differential memory performance. Neurobiol Dis. 2016 Feb;86:121-30.

Temporal lobe epilepsy patients differ substantially with respect to their cognitive performance as major comorbidity, but currently little is known about relevant molecular-genetic factors. The present data indicate that poor memory performance in patients with temporal lobe epilepsy strongly corresponds to distinctly altered neuronal transcript signatures, which can correlate with a particular allelic promoter variant such as in the BIN1 gene, major component of the endocytotic machinery. Respective gene signatures may serve as biomarkers for impaired memory performance and derived future tailor made therapy development of this severe comorbidity.

Twele F, Töllner K, Bankstahl M, Löscher W. The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain. Epilepsia Open. 2016, 1: 45–60.

Mice developing spontaneous recurrent nonconvulsive and convulsive seizures after intrahippocampal injection of kainate are thought to represent a valuable model of mesial temporal lobe epilepsy. Epileptic EEG activity recorded in this model from the kainate focus in the ipsilateral hippocampus is resistant to anti-seizure drugs such as carbamazepine (CBZ). We compared the efficacy of CBZ in this model in two different mouse strains (FVB/N and NMRI). Furthermore, we evaluated whether changes in the definition of electrographic seizures affect the anti-seizure efficacy of CBZ. As in previous studies, two types of epileptic EEG activity were defined: high-voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs). The characteristics of these paroxysmal EEG events in epileptic mice were compared with EEG criteria for nonconvulsive seizures in patients. For HVSWs, different spike frequencies, inter-event intervals, and amplitudes were used as inclusion and exclusion criteria. Slight changes in HVSW definition determined whether they were resistant or responsive to CBZ. HVSWs were more resistant than HPDs to suppression by CBZ. Both types of epileptic EEG activity were rapidly suppressed by diazepam and phenobarbital. The data demonstrate that focal electrographic seizures in the intrahippocampal kainate mouse model are less resistant than previously thought. Both mouse strain and the criteria chosen for definition of EEG seizures determine whether such seizures are drug-resistant or -responsive.

EPITARGET publications recently accepted for publication/in press

Srivastava PK, Bagnati M, Delahaye-Duriez A, Ko J-H, Rotival M, Langley SR, Shkura K, Mazzuferi M, Danis B, van Eyll J, Foerch P, Behmoaras J, Kaminski RM, Petretto E, Johnson MR. Genome-wide analysis of differential RNA editing in epilepsy. Genome Research 2017, in press.

Symonds JD, Zuberi SM, Johnson MR. Advances in epilepsy gene discovery and the implications for epilepsy diagnosis and treatment. Current Opinion in Neurology 2017, in press.

Scott G, Mahmud M, Owen DR, Johnson MR. Microglial positron emission tomography (PET) imaging in epilepsy: applications, opportunities and pitfalls. Seizure European Journal of Epilepsy 2016.

Delahaye-Duriez A, Srivastava P, Shkura K, Langley SR, Laaniste L, Moreno-Moral A, Danis B, Mazzuferi m, Foerch P, Gazina EV, Richards K, Petrou S, Kaminski R, Petretto E, Johnson MR. Rare and common epilepsies converge on a shared gene regulatory network: opportunities for novel antiepileptic drug discovery. Genome Biology 2016, 13;17(1):245.

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EPITARGET presentations - a selection

J.A. Gorter (AMC). Rapamycin effects on BBB leakage, inflammation, epileptogenesis and seizures. Immunity and Inflammation Meeting 2016, Milan, Italy, October 14, 2016.

E. Aronica (AMC). Epigenetic control of neuroinflammation: miRNAs and epileptogenesis. Immunity and Inflammation Meeting 2016, Milan, Italy, October 14, 2016.

E. Aronica (AMC). New challenges in FCD: molecular mechanisms of epileptogenesis. 12th European Congress on Epileptology, Prague, Czech Republic, September 14, 2016.

E.A. van Vliet (AMC). mTOR inhibition to restore blood-brain barrier leakage in epilepsy. 12th European Congress on Epileptology, Prague, Czech Republic, September 15, 2016.

A. Vezzani (IRFMN). microRNA and inflammation: new therapeutic opportunities in epilepsy associated pathologies. 31st European Epilepsy Congress (ECE), 11-15 September 2016, Prague, Czech Republic.

A. Vezzani (IRFMN). Disulfide HMGB1 is generated by oxidative stress in the rat hippocampus during epileptogenesis and represents a novel mechanism of disease onset an progression. 31st European Epilepsy Congress (ECE), 11-15 September 2016, Prague, Czech Republic.

R. Ravizza (IRFMN). In vivo biomarkers of neuroinflammation: can they track disease progression?. 31st European Epilepsy Congress (ECE), 11-15 September 2016, Prague, Czech Republic.

T. Ravizza (IRFMN). Targeting IL-1beta and HMGB1 with drug combinations. 70th American Epilepsy Society annual meeting, 2-6 December 2016, Houston, Texas, USA.

M. Simonato (UNIFER). miRNAs in comorbid epilepsy and depression. Conference "Novel treatment and re-habilitation strategies for neurological disorders and their comorbidities", June 11, 2016, Tbilisi, Georgia.

Presentations at the 2nd EPITARGET Young Researchers’ Symposium in Marseille- the list of presentations including the abstracts can be found in the undefinedabstract booklet.

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EPITARGET posters - a selection

van Scheppingen J, Iyer AM, Anink JJ, Mühlebner A, Scholl T, Jansen FE, Spliet WG, Buccoliero AM, Giordano F, Genitori L, Kotulska K, Jozwiak S, Jaworski J, Liszewska E, van Vliet EA, Aronica A. Expression of inflammation related microRNAs miR21, miR146a and miR155 in tuberous sclerosis complex cortical tubers and their modulation in SEGA cell cultures. Immunity and Inflammation Meeting 2016, Milan, Italy, October 13-15, 2016.

Drion CM, Kooijman L, van Vliet EA, Aronica E, Gorter JA. The effect of rapamycin and curcumin on inflammatory markers in the post status epilepticus rat model for temporal lobe epilepsy. Immunity and Inflammation Meeting 2016, Milan, Italy, October 13-15, 2016.

Roncon P (UNIFER). Meta-analysis of microRNAs dys-regulated in different models of epilepsy. FENS meeting. July 3, 2016, Copenhagen, Denmark.

Poster presentations at the 2nd EPITARGET Young Researchers’ Symposium in Marseille - the list of posters including the abstracts can be found in the undefinedabstract booklet.

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EPITARGET is a Collaboration Project funded by the European Union under the 7th Framework Programme under grant agreement n° 602102. Copyright | Imprint

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