γ-Aminobutyric acid transporter and GABA receptor mechanisms in and mice associated with developmental and epileptic encephalopathies.

We have previously characterized the molecular mechanisms for variants in γ-aminobutyric acid transporter 1-encoding solute carrier family 6-member 1 () and concluded that a partial or complete loss of γ-aminobutyric acid uptake due to impaired protein trafficking is the primary aetiology. Impairment of γ-aminobutyric acid transporter 1 function could cause compensatory changes in the expression of γ-aminobutyric acid receptors, which, in turn, modify disease pathophysiology and phenotype. Here we used different approaches including radioactive H γ-aminobutyric acid uptake in cells and synaptosomes, immunohistochemistry and confocal microscopy as well as brain slice surface protein biotinylation to characterize and mice, representative of a partial or a complete loss of function of mutations, respectively.

Spatial omics reveals molecular changes in focal cortical dysplasia type II.

Focal cortical dysplasia (FCD) represents a group of diverse localized cortical lesions that are highly epileptogenic and occur due to abnormal brain development caused by genetic mutations, involving the mammalian target of rapamycin (mTOR). These somatic mutations lead to mosaicism in the affected brain, posing challenges to unravel the direct and indirect functional consequences of these mutations. To comprehensively characterize the impact of mTOR mutations on the brain, we employed here a multimodal approach in a preclinical mouse model of FCD type II (Rheb), focusing on spatial omics techniques to define the proteomic and lipidomic changes.

Identification of gene regulatory networks affected across drug-resistant epilepsies.

Epilepsy is a chronic and heterogenous disease characterized by recurrent unprovoked seizures, that are commonly resistant to antiseizure medications. This study applies a transcriptome network-based approach across epilepsies aiming to improve understanding of molecular disease pathobiology, recognize affected biological mechanisms and apply causal reasoning to identify therapeutic hypotheses. This study included the most common drug-resistant epilepsies (DREs), such as temporal lobe epilepsy with hippocampal sclerosis (TLE-HS), and mTOR pathway-related malformations of cortical development (mTORopathies).

Astroglial calcium signaling and homeostasis in tuberous sclerosis complex.

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities.

Downregulation of Ubiquitin-Specific Protease 15 (USP15) Does Not Provide Therapeutic Benefit in Experimental Mesial Temporal Lobe Epilepsy.

Structural epilepsies display complex immune activation signatures. However, it is unclear which neuroinflammatory pathways drive pathobiology. Transcriptome studies of brain resections from mesial temporal lobe epilepsy (mTLE) patients revealed a dysregulation of transforming growth factor β, interferon α/β, and nuclear factor erythroid 2-related factor 2 pathways.

Shaping the future of European epilepsy research: Final meeting report from EPICLUSTER.

Collaboration is essential to the conduct of basic, applied and clinical research and its translation into the technologies and treatments urgently needed to improve the lives of people living with brain diseases and the health professionals who care for them. EPICLUSTER was formed in 2019 by the European Brain Research Area (EBRA) to support the coordination of epilepsy research in Europe. A key objective was to provide a platform to discuss shared research priorities by bringing together scientists and clinicians with multiple stakeholders including patient organisations and industry and the networks and infrastructures that provide healthcare and support research.

Characterising seizure development, behavioural comorbidities and neuroinflammation in a self-sustained electrical status epilepticus model of mesial temporal lobe epilepsy in C57BL/6J mice.

Objective: Status epilepticus (SE) models in rodents are commonly used to research mesial temporal lobe epilepsy (mTLE) in translational epilepsy research. However, due to differences in susceptibility of mice strains to chemoconvulsants, developing this model in mice is challenging. Mice offer experimental advantages; in particular, the ability to use transgenic strains could provide novel insights about neurobiological mechanisms or ease of genetic modification to test potential therapeutic targets.

Seizure-mediated iron accumulation and dysregulated iron metabolism after status epilepticus and in temporal lobe epilepsy.

Neuronal dysfunction due to iron accumulation in conjunction with reactive oxygen species (ROS) could represent an important, yet underappreciated, component of the epileptogenic process. However, to date, alterations in iron metabolism in the epileptogenic brain have not been addressed in detail. Iron-related neuropathology and antioxidant metabolic processes were investigated in resected brain tissue from patients with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), post-mortem brain tissue from patients who died after status epilepticus (SE) as well as brain tissue from the electrically induced SE rat model of TLE.

What value can TSPO PET bring for epilepsy treatment?

Epilepsy is one of the most common neurological disorders and affects both the young and adult populations. The question we asked for this review was how positron emission tomography (PET) imaging with translocator protein (TSPO) radioligands can help inform the epilepsy clinic and the development of future treatments targeting neuroinflammatory processes.Even though the first TSPO PET scans in epilepsy patients were performed over 20 years ago, this imaging modality has not seen wide adoption in the clinic.

TSPO PET upregulation predicts epileptic phenotype at disease onset independently from chronic TSPO expression in a rat model of temporal lobe epilepsy.

Neuroinflammation is a key component of epileptogenesis, the process leading to acquired epilepsy. In recent years, with the development of non-invasive in vivo positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO), a marker of neuroinflammation, it has become possible to perform longitudinal studies to characterize neuroinflammation at different disease stages in animal models of epileptogenesis. This study aimed to utilize the prognostic capability of TSPO PET imaging at disease onset (2 weeks post-SE) to categorize epileptic rats with distinct seizure burden based on TSPO levels at disease onset and investigate their association to TSPO expression at the chronic epilepsy stage.

Balloon cells promote immune system activation in focal cortical dysplasia type 2b.

Aims: Focal cortical dysplasia (FCD) type 2 is an epileptogenic malformation of the neocortex associated with somatic mutations in the mammalian target of rapamycin (mTOR) pathway. Histopathologically, FCD 2 is subdivided into FCD 2a and FCD 2b, the only discriminator being the presence of balloon cells (BCs) in FCD 2b. While pro-epileptogenic immune system activation and inflammatory responses are commonly detected in both subtypes, it is unknown what contextual role BCs play.

WONOEP appraisal: Network concept from an imaging perspective.

Neuroimaging techniques applied to a variety of organisms-from zebrafish, to rodents to humans-can offer valuable insights into neuronal network properties and their dysfunction in epilepsy. A wide range of imaging methods used to monitor neuronal circuits and networks during evoked seizures in animal models and advances in functional magnetic resonance imaging (fMRI) applied to patients with epilepsy were discussed during the XIV Workshop on Neurobiology of Epilepsy (XIV WONOEP) organized in 2017 by the Neurobiology Commission of the International League Against Epilepsy (ILAE). We review the growing number of technological approaches developed, as well as the current state of knowledge gained from studies applying these advanced imaging approaches to epilepsy research.

The effect of pharmacological inhibition of Serine Proteases on neuronal networks .

Neurons are embedded in an extracellular matrix (ECM), which functions both as a scaffold and as a regulator of neuronal function. The ECM is in turn dynamically altered through the action of serine proteases, which break down its constituents. This pathway has been implicated in the regulation of synaptic plasticity and of neuronal intrinsic excitability.

Spatiotemporal expression and inhibition of prolyl oligopeptidase contradict its involvement in key pathologic mechanisms of kainic acid-induced temporal lobe epilepsy in rats.

Objective: Prolyl oligopeptidase (PREP) has been implicated in neuroinflammatory processes and neuroplasticity and has been suggested as a target for the treatment of neurodegenerative disease. The aim of this investigation was to explore the involvement of PREP in the neuropathologic mechanisms relevant to temporal lobe epilepsy (TLE) using a PREP inhibitor in a well-established rat model.

Methods: PREP activity and expression was studied in Sprague-Dawley rats 2 and 12 weeks following kainic acid-induced status epilepticus (KASE).

Hypersynchronicity in the default mode-like network in a neurodevelopmental animal model with relevance for schizophrenia.

Background: Immune activation during pregnancy is an important risk factor for schizophrenia. Brain dysconnectivity and NMDA receptor (NMDAR) hypofunction have been postulated to be central to schizophrenia pathophysiology. The aim of this study was to investigate resting-state functional connectivity (resting-state functional MRI-rsfMRI), microstructure (diffusion tension imaging-DTI) and response to NMDAR antagonist (pharmacological fMRI-phMRI) using multimodal MRI in offspring of pregnant dams exposed to immune challenge (maternal immune activation-MIA model), and determine whether these neuroimaging readouts correlate with schizophrenia-related behaviour.

In vivo measurement of brain network connectivity reflects progression and intrinsic disease severity in a model of temporal lobe epilepsy.

Different types of brain injury, such as status epilepticus (SE), trauma, or stroke may initiate the process of epileptogenesis and lead to the development of temporal lobe epilepsy. Epileptogenesis is characterized by an initial latent period during which impaired network communication and synaptic circuit alterations are occurring. Ultimately, these modifications result in the development of spontaneous recurrent seizures (SRS).

A companion to the preclinical common data elements for physiologic data in rodent epilepsy models. A report of the TASK3 Physiology Working Group of the ILAE/AES Joint Translational Task Force.

The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force created the TASK3 working groups to create for various aspects of preclinical epilepsy research studies, which could help improve standardization of experimental designs

Neuroimaging of Subacute Brain Inflammation and Microstructural Changes Predicts Long-Term Functional Outcome after Experimental Traumatic Brain Injury.

There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to controlled cortical impact (CCI) injury, sham surgery, or skin incision (naïve).

Kainic Acid-Induced Post-Status Epilepticus Models of Temporal Lobe Epilepsy with Diverging Seizure Phenotype and Neuropathology.

The aim of epilepsy models is to investigate disease ontogenesis and therapeutic interventions in a consistent and prospective manner. The kainic acid-induced (KASE) rat model is a widely used, well-validated model for temporal lobe epilepsy (TLE). As we noted significant variability within the model between labs potentially related to the rat strain used, we aimed to describe two variants of this model with diverging seizure phenotype and neuropathology.

Decreased levels of active uPA and KLK8 assessed by [ In]MICA-401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy.

Objective: Urokinase-type plasminogen activator (uPA) and kallikrein-related peptidase 8 (KLK8) are serine proteases that contribute to extracellular matrix (ECM) remodeling after brain injury. They can be labelled with the novel radiotracer [ In]MICA-401. As the first step in exploring the applicability of [ In]MICA-401 in tracing the mechanisms of postinjury ECM reorganization in vivo, we performed in vitro and ex vivo studies, assessing [ In]MICA-401 distribution in the brain in two animal models: kainic acid-induced status epilepticus (KASE) and controlled cortical impact (CCI)-induced traumatic brain injury (TBI).

Neuroimaging in animal models of epilepsy.

Epilepsy is one of the most common chronic neurological conditions worldwide. The current poor understanding and lack of reliable biomarkers of the epileptogenic process are the major limitations in the development of anti-epileptic drugs that are able to prevent or modify the underlying disease. The rapid progress in advanced imaging technologies has expanded our opportunities to study the disease in animal models of epilepsy by means of non-invasive research tools.

Neuroinflammation imaging markers for epileptogenesis.

Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression.

Intracerebral delivery of the M2 polarizing cytokine interleukin 13 using mesenchymal stem cell implants in a model of temporal lobe epilepsy in mice.

Objectives: Neuroinflammation plays a critical role in the pathophysiology of mesial temporal lobe epilepsy. We aimed to evaluate whether intracerebral transplantation of interleukin 13-producing mesenchymal stem cells (IL-13 MSCs) induces an M2 microglia/macrophage activation phenotype in the hippocampus with an epileptogenic insult, thereby providing a neuroprotective environment with reduced epileptogenesis.

Methods: Genetically engineered syngeneic IL-13 MSCs or vehicle was injected within the hippocampus 1 week before the intrahippocampal kainic acid-induced status epilepticus (SE) in C57BL/6J mice.