Why Malformations of Cortical Development Cause Epilepsy

Malformations of cortical development (MCDs), a complex family of rare disorders, result from alterations of one or combined developmental steps, including progenitors proliferation, neuronal migration and differentiation. They are an important cause of childhood epilepsy and frequently associate cognitive deficits and behavioral alterations. Though the physiopathological mechanisms of epilepsy in MCD patients remain poorly elucidated, research during the past decade highlighted the contribution of some factors that will be reviewed in this paper and that include: (i) the genes that caused the malformation, that can be responsible for a significant reduction of inhibitory cells (e.g., ARX gene) or be inducing cell-autonomous epileptogenic changes in affected neurons (e.g., mutations on the mTOR pathway); (ii) the alteration of cortical networks development induced by the malformation that will also involve adjacent or distal cortical areas apparently sane so that the epileptogenic focus might be more extended that the malformation or even localized at distance from it; (iii) the normal developmental processes that would influence and determine the onset of epilepsy in MCD patients, particularly precocious in most of the cases

Conséquences physiopathologiques des mutations du gène ARX dans le développement cérébral

Des mutations du gène ARX (aristaless-related homeobox gene) ont été identifiées dans un large spectre de désordres neurologiques précoces, incluant ou non des malformations cérébrales, le plus souvent associés à des épilepsies. Il est proposé que le gène ARX, codant pour un facteur de transcription, joue un rôle primordial au cours du développement cérébral, notamment sur la migration des neurones GABAergiques, mais son implication au cours de la mise en place du système nerveux central reste cependant encore mal connue. L objectif de ce travail a été d étudier le rôle du gène ARX et les conséquences de ses mutations sur le développement cérébral dans le but de mieux comprendre ces pathologies. Dans un premier temps, nous avons étudié l effet d une mutation particulière du gène, la mutation ARX(CGC)7, une expansion polyalanine retrouvée principalement dans des pathologies sans malformation cérébrale mais avec des épilepsies, tels que les syndromes de West ou d Ohtahara. Des analyses réalisées sur une lignée de souris knock-in pour cette mutation (GCG)7 et sur des rats après électroporation in utero ont montré que la migration neuronale des neurones glutamatergiques et GABAergiques ainsi que la maturation des neurones GABAergiques ne sont pas altérées par cette mutation. De façon intéressante, nos données suggèrent que les épilepsies observées chez les souris knock-in résulteraient plutôt d une réorganisation du réseau glutamatergique. Etant donné que le gène ARX n est pas exprimé dans les neurones glutamatergiques, l ensemble de ce travail suggère donc que les épilepsies chez les souris knock-in pour la mutation (GCG)7 sont la conséquence d une altération développementale secondaire à la mutation initiale du gène, et ceci aurait d importantes répercussions thérapeutiques qui requièrent d avantages d études. Des expériences nous ont ensuite permis d étudier l effet de plusieurs mutations du gène ARX sur la morphologie des interneurones in vitro. Celles-ci ont montré que les mutations d ARX n engendrent pas une localisation subcellulaire anormale de la protéine dans les interneurones en culture. De façon intéressante, ces expériences suggèrent que la morphologie des interneurones est altérée seulement par certaines mutations, notamment les mutations P353R et Dup24. Ces données soulignent ainsi l importance d étudier de façon spécifique chaque mutation du gène pour expliquer les mécanismes engendrant l hétérogénéité phénotypique liée aux mutations d ARX. L ensemble de ces travaux contribuent à une meilleure compréhension du rôle du gène ARX dans le développement cortical et à une meilleure caractérisation des mécanismes physiopathologiques des désordres neurologiques précoces liés aux mutations de ce gène.Several mutations in ARX gene (aristaless-related homeobox gene) have been found in a large spectrum of infantile neurological disorders, with or without cerebral malformation, but frequently linked to epilepsy. It has been proposed that ARX, coding for a transcription factor, plays a crucial role in brain development, especially in migrating interneurons, but its involvement in nervous system development still remains to be clarified. The aim of this work has been to study the role of ARX gene and the consequences of ARX mutations on cerebral development in order to better understand these pathologies.We have first investigated the effects of an ARX polyalanine expansion, the mutation (GCG)7, which was found in pathologies without brain malformation but associated to epilepsy, such as West and Ohtahara syndromes. Analysis performed on knock-in mice for this mutation and in utero electroporated rat brains have shown that this mutation doesn t alter neither glutamatergic and GABAergic neuronal migration, nor GABAergic neuron maturation. Interestingly, our data suggest that epilepsy observed in knock-in mice would result rather from a reorganization of glutamatergic networks. Since ARX gene is not expressed in excitatory neurons, our work suggests that epilepsy observed in knock-in mice is the consequence of developmental alterations secondary to the initial mutation, and this would have crucial therapeutic implications that require additional investigations. In vitro experiments have then allowed us to study the effect of several ARX mutations on interneurons morphology. These experiments have shown no abnormal subcellular localization of ARX protein following transfection of these different mutations in cultured interneurons. Interestingly, our data show that interneuron morphology is altered only by some mutations, particularly the P353R and the Dup24 ARX mutations. Our data underline the importance to study specifically each mutation in order to explain mechanisms generating phenotypic heterogeneity linked to ARX mutations.Taken together, this study contributes to a better understanding of ARX involvement in cerebral development and to a better characterization of pathophysiological mechanisms linked to ARX mutations.AIX-MARSEILLE2-Bib.electronique (130559901) / SudocSudocFranceF

Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat.

International audienceBACKGROUND AND PURPOSE: The contribution of inflammatory response to the pathogenesis of ischemic lesions in the neonate is still uncertain. This study described the chronological sequence of inflammatory changes that follow cerebral ischemia with reperfusion in the neonatal P7 rat. METHODS: P7 rats underwent left middle cerebral artery electrocoagulation associated with 1-hour left common carotid artery occlusion. The spatiotemporal pattern of cellular responses was characterized immunocytochemically with the use of antibodies against rat endogenous immunoglobulins to visualize the area of the breakdown of the blood-brain barrier. Infiltration of neutrophils and T lymphocytes was demonstrated by antibodies against myeloperoxidase and a pan-T cell marker, respectively. Antibodies ED1 and OX-42 were applied to identify microglial cells and macrophages. The response of astrocytes was shown with antibodies against glial fibrillary acidic protein. Cell survival was assessed by Bcl-2 expression. Cell death was demonstrated by DNA fragmentation with the use of the terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) assay and Bax immunodetection. RESULTS: Endogenous immunoglobulin extravasation through the blood-brain barrier occurred at 2 hours of recirculation and persisted until 1 month after ischemia. Neutrophil infiltration began at 24 hours and peaked at 72 to 96 hours (30+/-3.4 neutrophils per 0.3 mm(2); P<0.0001), then disappeared at 14 days after ischemia. T cells were observed between 24 and 96 hours of reperfusion. Resident microglia-macrophages exhibited morphological remnants and expressed the cell death inhibitor Bcl-2 at 24 hours of recirculation. They became numerous within the next 48 hours and peaked at 7 days after ischemia. Phenotypic changes of resident astrocytes were apparent at 24 hours, and they proliferated between 48 hours and 7 days after ischemia. Progressively inflammatory cells showed DNA fragmentation and the cell death activator Bax expression. Cell elimination continued until there was a complete disappearance of the frontoparietal cortex. CONCLUSIONS: These data demonstrate that perinatal ischemia with reperfusion triggers acute inflammatory responses with granulocytic cell infiltration, which may be involved in accelerating the destructive processes

A Parturition-Associated Nonsynaptic Coherent Activity Pattern in the Developing Hippocampus

SummaryCorrelated neuronal activity is instrumental in the formation of networks, but its emergence during maturation is poorly understood. We have used multibeam two-photon calcium microscopy combined with targeted electrophysiological recordings in order to determine the development of population coherence from embryonic to postnatal stages in the hippocampus. At embryonic stages (E16–E19), synchronized activity is absent, and neurons are intrinsically active and generate L-type channel-mediated calcium spikes. At birth, small cell assemblies coupled by gap junctions spontaneously generate synchronous nonsynaptic calcium plateaus associated to recurrent burst discharges. The emergence of coherent calcium plateaus at birth is controlled by oxytocin, a maternal hormone initiating labour, and progressively shut down a few days later by the synapse-driven giant depolarizing potentials (GDPs) that synchronize the entire network. Therefore, in the developing hippocampus, delivery is an important signal that triggers the first coherent activity pattern, which is silenced by the emergence of synaptic transmission

Basic mechanisms of MCD in animal models.

International audienceEpilepsy-associated glioneuronal malformations (malformations of cortical development [MCD]) include focal cortical dysplasias (FCD) and highly differentiated glioneuronal tumors, most frequently gangliogliomas. The neuropathological findings are variable but suggest aberrant proliferation, migration, and differentiation of neural precursor cells as essential pathogenetic elements. Recent advances in animal models for MCDs allow new insights in the molecular pathogenesis of these epilepsy-associated lesions. Novel approaches, presented here, comprise RNA interference strategies to generate and study experimental models of subcortical band heterotopia and study functional aspects of aberrantly shaped and positioned neurons. Exciting analyses address impaired NMDA receptor expression in FCD animal models compared to human FCDs and excitatory imbalances in MCD animal models such as lissencephaly gene ablated mice as well as in utero irradiated rats. An improved understanding of relevant pathomechanisms will advance the development of targeted treatment strategies for epilepsy-associated malformations

Daily Concentrations of PM2.5 in the Valencian Community Using Random Forest for the Period 2008–2018

Fine particulate matter (PM2.5) is a global problem that affects the population health and contributes to climate change. Remote sensing provides useful information for the development of air quality models. This work aims to obtain a daily model of PM2.5 levels in the Valencian Community with a resolution of 1 km for the period 2008–2018. MODIS-MAIAC images, meteorological parameters of the MERRA-2 project, land cover information and ground level measurements of PM2.5 levels were analysed with Random Forest. The verification of the model was carried out using cross-validation repeated ten times, and an evaluation of a test set with 20% of the collected information. The final model was used to generate maps of the daily concentrations of PM2.5 for the area of the Valencian Community throughout the study period.Centro de Investigaciones del Medioambient

Electrifying Ba0.5Sr0.5Co0.8Fe0.2O3-δ; for focalized heating in oxygen transport membranes

[EN] Industry decarbonization requires the development of highly efficient and flexible technologies relying on renewable energy resources, especially biomass and solar/wind electricity. In the case of pure oxygen production, oxygen transport membranes (OTMs) appear as an alternative technology for the cryogenic distillation of air, the industrially-established process of producing oxygen. Moreover, OTMs could provide oxygen from different sources (air, water, CO2, etc.), and they are more flexible in adapting to current processes, producing oxygen at 700-1000 degrees C. Furthermore, OTMs can be integrated into catalytic membrane reactors, providing new pathways for different processes. The first part of this study was focused on electrification on a traditional OTM material (Ba(0.5)Sr(0.5)Co(0.8)Fe(0.2)O3(-delta)), imposing different electric currents/voltages along a capillary membrane. Thanks to the emerging Joule effect, the membrane-surface temperature and the associated O-2 permeation flux could be adjusted. Here, the OTM is electrically and locally heated and reaches 900 degrees C on the surface, whereas the surrounding of the membrane was maintained at 650 degrees C The O-2 permeation flux reached for the electrified membranes was similar to 3.7 NmL. min(-1) cm(2), corresponding to the flux obtained with an OTM non-electrified at 900 degrees C. The influence of depositing a porous Ce0.8Tb0.2O2-delta catalytic/protective layer on the outer membrane surface revealed that lower surface temperatures (830 degrees C) were detected at the same imposed electric power. Finally, the electrification concept was demonstrated in a catalytic membrane reactor (CMR) where the oxidative dehydrogenation of ethane (ODHE) was carried out. ODHE reaction is very sensitive to temperature, and here, we demonstrate an improvement of the ethylene yield by reaching moderate temperatures in the reaction chamber while the O-2 injection into the reaction can be easily fine-tuned.Financial support by the Spanish Ministry of Science (PID2022-139663OB-I00 and CEX2021-001230-S grant funded by MCIN/AEI/10.13039/501100011033) and with funding from NextGenerationEU (PRTR-C17.I1) within the Planes Complementarios con CCAA (Area of Green Hydrogen and Energy) and it has been carried out in the CSIC Interdisciplinary Thematic Platform (PTI+) Transición Energética Sostenible+ (PTI-TRANSENER+), and the Universitat Politècnica de València (UPV) is gratefully acknowledged. Also, we acknowledge the support of the Servicio de Microscopía Elcectronica of the UPV.Laqdiem-Marin, M.; García-Fayos, J.; Almar-Liante, L.; Carrillo-Del Teso, AJ.; Represa-Bullido, Á.; López Nieto, JM.; Escolástico Rozalén, S.... (2024). Electrifying Ba0.5Sr0.5Co0.8Fe0.2O3-δ; for focalized heating in oxygen transport membranes. Journal of Energy Chemistry. 91:99-110. https://doi.org/10.1016/j.jechem.2023.12.008991109

A Selective Interplay between Aberrant EPSPKA and INaP Reduces Spike Timing Precision in Dentate Granule Cells of Epileptic Rats

Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input–output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor–mediated excitatory postsynaptic potentials (EPSPKA) not observed in controls. We report that, in contrast to time-locked spikes generated by EPSPAMPA in control DGCs, aberrant EPSPKA are associated with long-lasting plateaus and jittered spikes during single-spike mode firing. This is mediated by a selective voltage-dependent amplification of EPSPKA through persistent sodium current (INaP) activation. In control DGCs, a current injection of a waveform mimicking the slow shape of EPSPKA activates INaP and generates jittered spikes. Conversely in epileptic rats, blockade of EPSPKA or INaP restores the temporal precision of EPSP–spike coupling. Importantly, EPSPKA not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through INaP activation. We conclude that a selective interplay between aberrant EPSPKA and INaP severely alters the temporal precision of EPSP–spike coupling in DGCs of chronic epileptic rats

Etude anatomique et autoradiographique du bourgeonnement reactif des fibres moussues de l'hippocampe apres epilepsie

SIGLEINIST T 77543 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc