Seizures

Slow brain rhythms, observed during slow-wave sleep or seizures, often coincide with oscillations in extracellular potassium levels. These rhythms have a lower frequency compared to a typical neuron’s tonic firing. Mechanisms organizing these rhythms are believed to rely on synaptic interactions within the network or intrinsic cellular voltage dynamics, likely a combination of both. This study focuses on single neurons that can produce slow rhythms, which in turn can organize slow rhythms in neural networks. Common theories attribute intrinsic slow bursting of neurons to ion channels with slow

Epilepsy, affecting over 70 million individuals worldwide, poses a significant risk of sudden death, known as SUDEP. The DEPDC5 gene is a common factor in familial focal epilepsy, with or without cortical malformations, and its pathogenic variants increase the susceptibility to SUDEP. This study aims to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for high-risk patients, and develop preventive interventions.Methods involved the targeted deletion of Depdc5 in nucleus tractus solitarius (NTS) neurons in the mouse brainstem, followed by the administra

Aims: Survivors of cerebral malaria (CM) might develop lifelong sequelae such as cognitive deficits, altered behaviour or epilepsy. Animal models are needed to understand the underlying pathophysiology and to develop preventive or ameliorating therapies. Therefore, in this study we aimed to establish a mouse model reflecting consequences of CM. Methods: To ensure survival, C57BL/6 mice infected with P. berghei ANKA (PbANKA) were closely monitored for parasitaemia and clinical signs of CM, and rescued by artesunate treatment. Following electrode implantation, repetitive EEG-video monitoring was

The sudden emergence of dangerous seizures is the defining feature of epilepsy, but how and when the brain changes dynamics remains enigmatic. From the perspective of dynamical systems theory, such critical transitions occur upon inconspicuous perturbations in highly interconnected systems presenting positive feedback loops and can be modeled as mathematical bifurcations between alternative regimes. Here, we sought to characterize dynamical signatures of impending seizures. We systematically verified the predictions of the model called ‘Epileptor’ that captures seizure dynamics in five differe

…characterized by many symptoms, with seizures being highly penetrant and debilitating. Previous research on the pathological characterization of AS model mice showed an increased seizure susceptibility as well as abnormally high levels of perineuronal net (PNN) fluorescence. Our project aims to determine whether the

…to epileptogenic brain insults and seizures observed in-vivo.Rat primary cortical cultures were exposed to 11 chemoconvulsants (4-aminopyridine, amoxapine, bicuculline, chlorpromazine, donepezil, kainic acid, pentylenetetrazol, picrotoxin, pilocarpine HCl, SNC80, strychnine HCl) for 24 h, followed by extraction of RNA for sequencing. Salmon tool quantified ncRNAs. DESeq2 analyzed differential expressions. qPCR validations for samples exposed to amoxapine, ch

Zebrafish is becoming an increasingly popular animal for modelling seizures and epilepsy. Various pharmacological and genetic models are utilized for both discovering new anti-epileptic drugs and for investigating fundamental mechanisms regulating neural excitability, seizures, and epilepsy. We aimed at developing multiple pharmacologically induced seizure and epilepsy models, in order to utilize these models for high-throughput behavioural screens and for functional brain imaging. We showed that several parameters of locomotor behaviours and spatial exploration are altered in seizure and epil

…Lindane induces seizures refractory to conventional antiepileptics. Delta sleep-inducing peptide (DSIP) is an endogenous peptide that is constantly present in several different brain regions showing neuroprotective The aim of our study was to examine the effects of DSIP supplementation on electroencephalographic (EEG) ictal activity induced by lindane in rats. Adult male rats with previously implanted electrode

Background: Epilepsy and seizures occurrence are closely interwoven with brain inflammation. The inflammatory response is largely mediated by microglia, which are under strong circadian regulation. Circadian rhythms are 24-hour variations in physiological function orchestrated by a network of autoregulatory genes, including its key component, Bmal1. Here we explored the impact of Bmal1 knock down in microglial cells on seizure susceptibility and the CNS-immune profile.Methods: Forty young adult Bmal1-Cx3CR1Cre-ER mice were injected with either tamoxifen (40 mg/kg; IP; daily for 10 days) to ind

Seizures produce autonomic symptoms, mainly sympathetic but also parasympathetic in origin. As the vagus nerve (VN) is the main parasympathetic output, the aims of the project is to characterize VN activity during seizures for potential future development closed-loop VNS.Spontaneous seizures were pharmacologically induced in two male Wistar rats (380±14g) by IP kainic acid systemic administration. Surgeries were performed three months after status induction. Three epidural electrodes were implanted for EEG recording. A tripolar Micro-cuff electrode was placed around the left cervical VN to rec

Primary mitochondrial diseases are caused by mutations in genes that perturb mitochondrial function and frequently affect the nervous system in patients. Complex I deficiency is the most common childhood mitochondrial disease and is caused by mutations in genes encoding complex I structural or assembly components. In patients, mutations in the complex I subunit NDUFS1 typically cause severe and rapidly progressive leukoencephalopathy and death during childhood. We developed a Drosophila model of complex I deficiency using knockdown of the NDUFS1 homolog ND-75 in neurons (ND-75 KD). ND-75 KD fl

…decline, many patients experience seizures which exacerbate the condition. Despite the recognised etiological overlaps between tauopathies and epilepsies, the relationship between tau and the development of circuit hyperexcitability is unclear and needs further investigation. Using wireless EEG to record intrahippocampal local field potentials (LFP), we characterised early biophysical alterations within the hippocampus of

…Neonatal homozygous (hom) mice showed seizures starting around P3, with heterozygous (het) mice also exhibiting early seizures. Despite recovery in het mice, persistent network alterations were obs

During life, a variety of specialized cells arise to grant the right and timely corrected functions of tissues and organs. Regulation of chromatin in defining specialized genomic regions (e.g. enhancers) plays a key role in developmental transitions from progenitors into cell lineages. These enhancers, properly topologically positioned in 3D space, ultimately guide the transcriptional programs. It is becoming clear that several pathologies converge in differential enhancer usage with respect to physiological situations. However, why some regulatory regions are physiologically preferred, while

…with tumor growth and occurrence of seizures affects glioma prognosis, while the developing tumor triggers seizures in the infiltrated cortex. Oncometabolites produced by tumor cells and neurotransmitters affect both the generation of epileptic activities by neurons and the growth of glioma cells through synaptic-related mechanisms, involving both GABAergic / Chloride pathways and glutamatergic signaling. From a clinical sight, epilepsy occurrenc

…that are recognisable as epileptic seizures. Yet usually, brain operate within certain constraints given through neuronal function and synaptic coupling, that will prevent epileptic seizure dynamics from emerging. In this talk, I will bring together different approaches to identifying how networks in the broadest sense shape brain dynamics. Using illustrative examples from intracranial EEG recordings, disorders characterised by molecular disruption of a single neurotransmitter receptor type, to single-cell r

Astroglia-neuron interactions are involved in multiple processes, regulating development, excitability and connectivity of neural circuits. Accumulating number of evidences highlight a direct connection between aberrant astroglial genetics and physiology in various forms of epilepsies. Using zebrafish seizure models, we showed that neurons and astroglia follow different spatiotemporal dynamics during transitions from pre-ictal to ictal activity. We observed that during pre-ictal period neurons exhibit local synchrony and low level of activity, whereas astroglia exhibit global synchrony and hig

Developmental epileptic encephalopathies are early-onset epilepsies, often refractory to therapy, with developmental delay or regression. These disorders carry poor neurodevelopmental prognosis, with long-term refractory epilepsy and persistent cognitive, behavioral and motor deficits. Mutations in the CACNA1A gene, encoding the pore-forming α1 subunit of CaV2.1 voltage-gated calcium channels, result in a spectrum of neurological disorders, including severe, early-onset epileptic encephalopathies. Recent work from the Rossignol lab helped characterize the phenotypic spectrum of CACNA1A-relate

…of cortical development (fMCD), and seizures in 80-90% of the patients. The current definitive treatments for epilepsy are surgical resection or treatment with everolimus, which inhibits mTOR activity (only approved for TSC). Because both options have severe limitations, there is a major need to better understand the mechanisms leading to seizures to improve life-long epilepsy treatment in TSC and FCDII. To investigate su

…result in deleterious outcomes such as seizures. In this talk, I will describe a mechanism for circuit-level adaptive regulation of cortical activity during macro-fluctuati

…in the generation and suppression of seizures have been widely studied. In my talk, I will address some fundamental issues which are relevant in this field of research: What are EGABA shifts about? What is the role of KCC2 in shunting inhibition? What is meant by “the balance between excitation and inhibition” and, in this con

Glioblastoma cells trigger pharmacoresistant seizures that may promote tumor growth and diminish the quality of remaining life. To define the relationship between growth of glial tumors and their neuronal microenvironment, and to identify genomic biomarkers and mechanisms that may point to better prognosis and treatment of drug resistant epilepsy in brain cancer, we are analyzing a new generation of genetically defined CRISPR/in utero electroporation inborn glioblastoma (GBM) tumor models engineered in mice. The molecular pathophysiology of glioblastoma cells and surrounding neurons and untra

The occurrence of seizures at specific times of the day has been consistently observed for centuries in individuals with epilepsy. Electrophysiological recordings provide evidence that seizures have a higher probability of occurring at a given time during the night and day cycle in individuals with epilepsy – the seizure rush hour. Which mechanisms underly such circadian rhythmicity of seizures? Why don’t they occur every day at the same time? Which mechanisms may underly their occurrence outside the rush hour? I shall present a hypothesis: MORE - Molecular Oscillations and Rhythmicity of Epil

Dravet syndrome is a severe childhood epilepsy due to heterozygous loss-of-function mutation of the gene SCN1A, which encodes the type 1 neuronal voltage gated sodium (Na+) channel alpha-subunit Nav1.1. Prior studies in mouse models of Dravet syndrome (Scn1a+/- mice) at early developmental time points indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons (INs) and, in particular, in parvalbumin-positive fast-spiking basket cells (PV-INs). This has led to a model of Dravet syndrome pathogenesis whereby Nav1.1 mutation leads to preferential IN dysfunction