Epileptogenesis

…seizures via a process called epileptogenesis. The aim of this study is to examine the plasma metabolomics profile in TLE-induced rats to find feasible biomarkers that can distinguish phases of epileptogenesis. Status epilepticus (SE) was induced by low-dose-repetitive-lithium chloride–pilocarpine hydrocholoride intraperitoneal injections. Control groups just received saline injections. Blood samples were collected 48 hours, 7 days and 6 weeks after SE, re

Epilepsy prevention is an urgent and global unmet need today. Particularly, in structural epilepsies that may occur months or even years after an epileptogenic insult (e.g., stroke, tumor, trauma, or status epilepticus), this latency time provides a window for preventive treatments for individuals at risk of developing epilepsy. In this regard, the identification of biomarkers to detect the subgroup of individuals with an increased risk of epilepsy after the epileptogenic insult is essential for the development of preventive treatments.A multicenter study was conducted using four different mod

Introduction: Epileptogenesis is the molecular and cellular process by which a healthy brain becomes an epileptic one. Some evidence suggests that the disruption of circadian rhythms may be impacting the epilepsy phenotype. However, whether the molecular clock is a key player in epileptogenesis remains to be elucidated. Here, we mapped for the first-time the hippocampal molecular rhythmicity of mice during epileptogenesis. Methods: Male adult C57BL/6 mice (n=5/group/Zeitgeber-Times [ZTs]) underwent intra-amygdala kainic acid-induced (i.a.KA) status epilepticus or control (i.a.PBS). From 24h af

Study objective was to evaluate whether seizure-inducing chemoconvulsants could induce dysregulation of non-coding RNAs (ncRNAs), similar 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

…pathomechanisms that occur during epileptogenesis, so between the transient hypoxia and the first late seizure.Some transcription factors drive gene-expression towards an epileptogenic phenotype through channelopathies, which may be acquired through brain insults, such as the T-type Ca2+ channel CaV3.2.Hypoxia-inducible factor 1α (HIF-1α) is quickly activated and can bind to the promoter of CaV3.2, potentially inducing an epileptogenic cascade in penumbra neurons.We used NS20Y cells and prima

…While PIP2's role in epileptogenesis is known, our study investigates the unclear role of PIP3 using PTZ-induced epileptic mice, exploring its impact on epileptogenesis and associated sleep disruptions. Methods: Our hypothesis proposed a pivotal role for PIP3 in the molecular mechanism of seizures. We intraperitoneal administered low dose of PTZ once every two

…SUDEP, but the network changes driving epileptogenesis during development are not known. Given the dominant role of Nav1.2 during hippocampal development we hypothesize th

Temporal lobe epilepsy (TLE) is one of the most common forms of drug-resistant epilepsy and its precise etiology is still unknown making it imperative to understand the molecular pathways contributing to the disease. It is, therefore, crucial to study the therapeutic targets and signalling pathways involved in the treatment of this disease. Pyk2 has previously been shown to be activated in stress-mediated pathways in the brain. Consequently, we hypothesized that Pyk2 activation might contribute to the pathogenesis of the disease. A pilocarpine model of TLE was used to examine p-Pyk2Tyr402 prot

…the specific contribution of Brg1 to epileptogenesis has not been well characterized. Using various tools, including pharmacological treatment, genomic manipulation with the CRISPR/Cas9 system in

…profiling study of lncRNAs during epileptogenesis and assess their utility as novel drug targets. Methods: To study lncRNA dysregulation, Next Generation Sequencing was performed on hippocampal tissue collected during

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. We developed a novel conditioned seizure memory (CSM) paradigm, in which seizures and specific cues were paired. The CSM could be reliably retrieved, demonstrating a robust association. We also found that activation of cue-responding engram cells in hippocampus DG could create artificial CSM. After seizure memory retrieval, a protein synthesis-dependent reconsolidation process invol

High-frequency oscillations (HFOs) have been observed to be particularly prominent in brain regions responsible for seizure initiation and propagation. Connexins play a crucial role in fast intercellular communication within the brain, as they are integral components of gap junctions, which facilitate direct cytoplasmic connections between neighboring cells. Recent studies identified clusters of connexins within the rodent CNS, specifically along the axon initial segment (AIS), a critical neuronal microdomain responsible for the initiation of action potentials. However, details about the subce

Our study investigates mechanisms of epileptogenesis caused by the p.A263V mutation in the SCN2A gene using a Scn2a p.A263V mouse model. The SCN2A gene is known for its role in neurodevelopmental disorders with epileptic presentations. Our objective is to understand the molecular foundations of neonatal neuronal hyperexcitability and its evolution into adult network disruptions, employing scRNA-seq. 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

Glioblastoma is a highly malignant tumor with poor prognosis. Intercellular signaling has been proposed to be directly involved in glioblastoma proliferation, motility and invasion. In particular, (i) glioblastoma growth and infiltration are associated to deregulated astrocytes-neuron signaling; (ii) glioblastoma induces astrocytes function alterations leading to modification of the inter and intra cellular communication and neuronal hyperactivity and epileptic seizures; (iii) glutamate release in peri-tumoral region excite glutamate receptors on glioma cells promoting tumor growth and invasiv

The epileptogenesis process is associated with large-scale changes in gene expression, which contribute to the remodelling of brain networks permanently altering excitability. About 80% of the protein coding genes are under the influence of the circadian rhythms. These are 24-hour endogenous rhythms that determine a large number of daily changes in physiology and behavior in our bodies. In the brain, the master clock regulates a large number of pathways that are important during epileptogenesis and established-epilepsy, such as neurotransmission, synaptic homeostasis, inflammation, blood-brain

Epileptogenesis is a gradual and dynamic process leading to difficult-to-treat seizures. Several cellular, molecular, and pathophysiologic mechanisms, including the activation of inflammatory processes. The use of human brain tissue represents a crucial strategy to advance our understanding of the underlying neuropathology and the molecular and cellular basis of epilepsy and related cognitive and behavioral comorbidities, The mounting evidence obtained during the past decade has emphasized the critical role of inflammation in the pathophysiological processes implicated in a large spectrum o

How seizures emerge from the abnormal dynamics of neural networks within the epileptogenic tissue remains an enigma. Are seizures random events, or do detectable changes in brain dynamics precede them? Are mechanisms of seizure emergence identical at the onset and later stages of epilepsy? Is the risk of seizure occurrence stable, or does it change over time? A myriad of questions about seizure genesis remains to be answered to understand the core principles governing seizure genesis. The last decade has brought unprecedented insights into the complex nature of seizure emergence. It is now bel

The origins, mechanisms and consequences of epilepsy in the developing brain are incompletely understood. Many developmental epilepsies have a genetic basis and their mechanisms stem from deficits in the function of one or numerous genes. Others, such as those that follow prolonged febrile seizures or severe birth asphyxia in a ‘normal’ brain may depend on the interaction of the insult with the rapidly evolving brain cells and circuits. Yet, how early-life insults may provoke epilepsy is unclear, and requires multiple levels of analysis: behavior, circuits, cells [neurons, glia] and molecules.

…of why and how the disease develops (epileptogenesis) remains elusive. Here, we present a first-of-its-kind model of epileptogenesis describing the interactions between neuroinflammation, blood-brain barrier disruption, neuronal death, circuit remodeling, and seizures. The model is formulated as a system of nonlinear differential equations describing processes acting on realistic timescales ranging from seconds to weeks. Mathematically, it is characterized by two stable fixed

…responses which contribute to epileptogenesis. I will present our recent studies identifying a role for neuro-immune interactions, specifically, the innate immune receptor Toll-like receptor 4 (TLR4), in enhancing network excitability and cell loss in hippocampal dentate gyrus early after concussive brain injury. I will describe results indicating that the transient post-traumatic increases in dentate neurogenesis which occurs during th

…mechanisms linking malformations to epileptogenesis remain elusive. In this seminar I will present

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