Hippocampe et épilepsie : données issues des tissus humains

International audienceSurgical removal of the epileptogenic zone provides an effective therapy for several focal epileptic syndromes. This surgery offers the opportunity to study pathological activity in living human tissue for pharmacoresistant partial epilepsy syndromes including temporal lobe epilepsies with hippocampal sclerosis, cortical dysplasias, epilepsies associated with tumors and developmental malformations. Slices of tissue from patients with these syndromes retain functional neuronal networks and may generate epileptic activities. The properties of cells in this tissue may not be greatly changed, but excitatory synaptic transmission is often enhanced and GABAergic inhibition is preserved. Typically epileptic activity is not generated spontaneously by the neocortex, whether dysplastic or not, but can be induced by convulsants. The initiation of ictal discharges in the neocortex depends on both GABAergic signaling and increased extracellular potassium. In contrast, a spontaneous interictal-like activity is generated by tissues from patients with temporal lobe epilepsies associated with hippocampal sclerosis. This activity is initiated, not in the hippocampus but in the subiculum, an output region, which projects to the entorhinal cortex. Interictal events seem to be triggered by GABAergic cells, which paradoxically excite about 20% of subicular pyramidal cells while simultaneously inhibiting the majority. Interictal discharges thus depend on both GABAergic and glutamatergic signaling. The depolarizing effects of GABA depend on a pathological elevation in levels of chloride in some subicular cells, similar to those of developmentally immature cells. Such defect is caused by a perturbed expression of the cotransporters regulating intracellular chloride concentration, the importer NKCC1 and the extruder KCC2. Blockade of NKCC1 actions by the diuretic bumetanide restores intracellular chloride and thus hyperpolarizing GABAergic actions and consequently suppressing interictal activity.La résection chirurgicale de la zone épileptogène est la procédure thérapeutique de choix de multiples épilepsies focales. Elle permet d’étudier les activités pathologiques dans du tissu humain maintenu en vie in vitro pour divers syndromes épileptiques pharmacorésistantes dont les épilepsies temporales avec sclérose hippocampique, dysplasies corticales, autres malformations développementales ou tumeurs. In vitro, dans des tranches de tissu issues de pièces opératoires, le réseau épileptique est conservé et des activités épileptiques sont produites. À l’échelle neuronale, les propriétés intrinsèques semblent peu modifiées, certaines composantes synaptiques excitatrices glutamatergiques apparaissent renforcées et l’inhibition GABAergique est maintenue. Dans le néocortex, qu’il soit dysplasique ou non, une activité synchrone épileptiforme n’est généralement pas enregistrée spontanément mais doit être induite pharmacologiquement. L’initiation des décharges ictales implique alors la signalisation GABAergique et une augmentation de la concentration extracellulaire en potassium. Au sein de tissus provenant de patients souffrant d’épilepsies mésio-temporales associées à une sclérose hippocampique, une activité épileptiforme est recueillie spontanément. Il s’agit de bouffées interictales générées non pas dans l’hippocampe mais dans le subiculum, sa région de sortie interfacée avec le cortex entorhinal. Cette activité est initiée par la décharge d’interneurones qui excitent paradoxalement par le GABA libéré environ 1/5 des cellules pyramidales, hyperpolarisant les autres. Les décharges sont donc sous-tendues tant par la signalisation GABAergique que glutamatergique. L’origine des réponses dépolarisantes au GABA est une perturbation de l’homéostasie du chlore, secondaire à une modification de l’expression des co-transporteurs régulant sa concentration intracellulaire, NKCC1 et KCC2, évoquant un retour à un phénotype neuronal immature. La restauration d’une concentration normale en chlore en bloquant NKCC1 par le diurétique bumétanide permet ainsi de supprimer les activités interictales

Threshold Behavior in the Initiation of Hippocampal Population Bursts

SummaryHippocampal population discharges such as sharp waves, epileptiform firing, and GDPs recur at long and variable intervals. The mechanisms for their precise timing are not well understood. Here, we show that population bursts in the disinhibited CA3 region are initiated at a threshold level of population firing after recovery from a previous event. Each population discharge follows an active buildup period when synaptic traffic and cell firing increase to threshold levels. Single-cell firing can advance burst onset by increasing population firing to suprathreshold values. Population synchrony is suppressed when threshold frequencies cannot be reached due to reduced cellular excitability or synaptic efficacy. Reducing synaptic strength reveals partially synchronous population bursts that are curtailed by GABAB-mediated conductances. Excitatory glutamatergic transmission and delayed GABAB-mediated signals have opposing feedback effects on CA3 cell firing and so determine threshold behavior for population synchrony

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Étude par tomographie d'émission monophotonique (TEMP) de l'image en miroir dans les épilepsies partielles

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Genèse des activités épileptiques au sein des structures hippocampiques

Ce travail étudie l influence sur la genèse des activités épileptiques des interactions entre signalisations GABA et glutamatergique. Dans la région CA3, les activités interictales induites par disinhibition se mettent en place par des synchronisations partielles se sculptant par l induction de phases de silence GABAB. Chaque bouffée synchrone est déclenchée lorsque l excitation récurrente dépasse un seuil de fréquence de décharge, à laquelle s oppose l inhibition GABAB retardée. Au sein du tissu temporal épileptogène humain post opératoire, le subiculum génère spontanément une activité interictale sous-tendue par l excitation glutamatergique et des réponses dépolarisantes au GABA. Celles-ci sont liées à une altération de l homéostasie du Cl-, en relation avec une perturbation de l expression de ses co-transporteurs. Des activités ictales peuvent y être générées pharmacologiquement. La transition est caractérisée par l émergence d activités de population purement glutamatergique, les décharges préictales. Elles précèdent ensuite la crise, son initiation impliquant aussi la transmission GABAergique.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

GABAergic circuits drive focal seizures

Epilepsy is based on abnormal neuronal activities that have historically been suggested to arise from an excess of excitation and a defect of inhibition, or in other words from an excessive glutamatergic drive not balanced by GABAergic activity. More recent data however indicate that GABAergic signaling is not defective at focal seizure onset and may even be actively involved in seizure generation by providing excitatory inputs. Recordings of interneurons revealed that they are active at seizure initiation and that their selective and time-controlled activation using optogenetics triggers seizures in a more general context of increased excitability. Moreover, GABAergic signaling appears to be mandatory at seizure onset in many models. The main pro-ictogenic effect of GABAergic signaling is the depolarizing action of GABAA conductance which may occur when an excessive GABAergic activity causes Cl− accumulation in neurons. This process may combine with background dysregulation of Cl−, well described in epileptic tissues. Cl− equilibrium is maintained by (Na+)/K+/Cl− co-transporters, which can be defective and therefore favor the depolarizing effects of GABA. In addition, these co-transporters further contribute to this effect as they mediate K+ outflow together with Cl− extrusion, a process that is responsible for K+ accumulation in the extracellular space and subsequent increase of local excitability. The role of GABAergic signaling in focal seizure generation is obvious but its complex dynamics and balance between GABAA flux polarity and local excitability still remain to be established, especially in epileptic tissues where receptors and ion regulators are disrupted and in which GABAergic signaling rather plays a 2 faces Janus role

Cellular correlates of epileptic spikes with high-frequency oscillations in the human temporal lobe

International audienceThis scientific commentary refers to ‘Interictal spikes with and without high-frequency oscillation have different single-neuron correlates’ by Guth et al. (doi:10.1093/brain/awab288)

Inhibition and oscillations in the human brain tissue in vitro

Oscillations represent basic operational modes of the human brain. They reflect local field potential activity generated by the laminar arrangement of cell-type specific microcircuits interacting brain-wide under the influence of neuromodulators, endogenous processes and cognitive demands. Under neuropathological conditions, the spatiotemporal structure of physiological brain oscillations is disrupted as recorded by electroencephalography and event-relate potentials. Such rhythmopathies can be used to track microcircuit alterations leading not only to transient pathological activities such as interictal discharges and seizures but also to a range of cognitive co-morbidities. Here we review how basic oscillatory modes induced in human brain slices prepared after surgical treatment can help us to understand basic aspects of brain function and dysfunction. We propose to overcome the traditional view of examining human brain slices merely as generators of epileptiform activities and to integrate them in a more physiologically-oriented oscillatory framework to better understand mechanisms of the diseased human brain.We thank the Spanish Ministerio de Economía y Competitividad (BFU2015- 66887-R) and the Fundación Tatiana Perez de Guzman el Bueno for supporting grants to LMP

Adaptation and Inhibition Control Pathological Synchronization in a Model of Focal Epileptic Seizure

International audiencePharmacoresistant epilepsy is a common neurological disorder in which increased neuronal intrinsic excitability and synaptic excitation lead to pathologically synchronous behavior in the brain. In the majority of experimental and theoretical epilepsy models, epilepsy is associated with reduced inhibition in the pathological neural circuits, yet effects of intrinsic excitability are usually not explicitly analyzed. Here we present a novel neural mass model that includes intrinsic excitability in the form of spike-frequency adaptation in the excitatory population. We validated our model using local field potential (LFP) data recorded from human hippocampal/subicular slices. We found that synaptic conductances and slow adaptation in the excitatory population both play essential roles for generating seizures and pre-ictal oscillations. Using bifurcation analysis, we found that transitions towards seizure and back to the resting state take place via Andronov-Hopf bifurcations. These simulations therefore suggest that single neuron adaptation as well as synaptic inhibition are responsible for orchestrating seizure dynamics and transition towards the epileptic state

Animal models and human tissue compared to better understand and treat the epilepsies

International audienceAnimal models of human brain disorders permit researchers to explore disease mechanisms and to test potential therapies. However, therapeutic molecules derived from animal models often translate poorly to the clinic. Although human data may be more relevant, experiments on patients are constrained, and living tissue is unavailable for many disorders. Here, we compare work on animal models and on human tissue for three epileptic syndromes where human tissue is excised therapeutically: (1) acquired temporal lobe epilepsies, (2) inherited epilepsies associated with cortical malformations, and (3) peritumoral epilepsies. Animal models rest on assumed equivalencies between human brains and brains of mice, the most frequently used model animal. We ask how differences between mouse and human brains could influence models. General principles and compromises in model construction and validation are examined for a range of neurological diseases. Models may be judged on how well they predict novel therapeutic molecules or new mechanisms. The efficacy and safety of new molecules are evaluated in clinical trials. We judge new mechanisms by comparing data from work on animal models with data from work on patient tissue. In conclusion, we stress the need to cross-verify findings from animal models and from living human tissue to avoid the assumption that mechanisms are identical