Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy.

There are no pharmacological disease-modifying treatments with an enduring effect to mitigate the seizures and comorbidities of established chronic temporal lobe epilepsy (TLE). This study aimed to evaluate for disease modifying effects of sodium selenate treatment in the chronically epileptic rat post-status epilepticus (SE) model of drug-resistant TLE. Wistar rats underwent kainic acid-induced SE or sham. Ten-weeks post-SE, animals received sodium selenate, levetiracetam, or vehicle subcutaneousinfusion continuously for 4 weeks. To evaluate the effects of the treatments, one week of continuous video-EEG was acquired before, during, and 4, 8 weeks post-treatment, followed by behavioral tests. Targeted and untargeted proteomics and metabolomics were performed on post-mortem brain tissue to identify potential pathways associated with modified disease outcomes. Telomere length was investigated as a novel surrogate marker of epilepsy disease severity in our current study. The results showed that sodium selenate treatment was associated with mitigation of measures of disease severity at 8 weeks post-treatment cessation; reducing the number of spontaneous seizures (p< 0.05), cognitive dysfunction (p< 0.05), and sensorimotor deficits (p< 0.01). Moreover, selenate treatment was associated with increased protein phosphatase 2A (PP2A) expression, reduced hyperphosphorylated tau, and reversed telomere length shortening (p< 0.05). Network medicine integration of multi-omics/pre-clinical outcomes identified protein-metabolite modules positively correlated with TLE. Our results provide evidence that treatment with sodium selenate results in a sustained disease-modifying effect in chronically epileptic rats in the post-KA SE model of TLE, including improved comorbid learning and memory deficits.

According to the World Health Organization (WHO), there are around 50 million people with epilepsy worldwide. Although drugs are available to control epileptic seizures, these only provide symptomatic relief. They cannot prevent the condition from worsening, and if people with epilepsy stop taking their medication, there is no lasting effect on the severity or frequency of their seizures. Some epilepsy cases are also resistant to these drugs. This is particularly common in adults with temporal epilepsy, with 30% of people continuing to suffer with seizures despite receiving medication. Current treatments also have no effect on problems with learning, memory and mental health that sometimes accompany drug-resistant epilepsy. Previous studies in animals have identified some potential treatments that could slow the progression of temporal epilepsy, but these have only been shown to work when used at a very early stage. Since most individuals with temporal epilepsy have already started having seizures when they are diagnosed (and it is difficult to predict who will develop the condition), these drugs are unlikely to be useful in practice. Here, Casillas-Espinosa et al. set out to find if a novel drug called sodium selenate can stop the progression of epilepsy and reduce the severity of temporal epilepsy when the condition is fully advanced. To do this, they used an animal model of temporal epilepsy, where rats had been modified to develop spontaneous seizures, resistance to normal anti-seizure medications, and problems with learning and memory. Casillas-Espinosa et al. found that sodium selenate not only reduced the number and severity of seizures in these model rats, but also improved their memory and learning ability. Several rats stopped having seizures altogether even after the treatment had stopped, indicating that sodium selenate had a long-lasting protective effect. Genetic analysis of the rats also revealed that shorter telomeres (special DNA sequences at the ends of chromosomes) correlated with increasing severity of the condition, suggesting that telomere length could help predict who might develop temporal epilepsy or respond best to treatment. This study identifies sodium selenate as a potential treatment that could reverse the progression of temporal epilepsy, even in individuals with advanced symptoms. Later this year, sodium selenate will be trialled in people with drug-resistant temporal epilepsy to determine if the drug benefits humans in the same way. Casillas-Espinosa et al. hope that it will improve participants' epilepsy and, ultimately, their quality of life.

An Integrated Multi-Omic Network Analysis Identifies Seizure-Associated Dysregulated Pathways in the GAERS Model of Absence Epilepsy.

Absence epilepsy syndromes are part of the genetic generalized epilepsies, the pathogenesis of which remains poorly understood, although a polygenic architecture is presumed. Current focus on single molecule or gene identification to elucidate epileptogenic drivers is unable to fully capture the complex dysfunctional interactions occurring at a genetic/proteomic/metabolomic level. Here, we employ a multi-omic, network-based approach to characterize the molecular signature associated with absence epilepsy-like phenotype seen in a well validated rat model of genetic generalized epilepsy with absence seizures. Electroencephalographic and behavioral data was collected from Genetic Absence Epilepsy Rats from Strasbourg (GAERS, n = 6) and non-epileptic controls (NEC, n = 6), followed by proteomic and metabolomic profiling of the cortical and thalamic tissue of rats from both groups. The general framework of weighted correlation network analysis (WGCNA) was used to identify groups of highly correlated proteins and metabolites, which were then functionally annotated through joint pathway enrichment analysis. In both brain regions a large protein-metabolite module was found to be highly associated with the GAERS strain, absence seizures and associated anxiety and depressive-like phenotype. Quantitative pathway analysis indicated enrichment in oxidative pathways and a downregulation of the lysine degradation pathway in both brain regions. GSTM1 and ALDH2 were identified as central regulatory hubs of the seizure-associated module in the somatosensory cortex and thalamus, respectively. These enzymes are involved in lysine degradation and play important roles in maintaining oxidative balance. We conclude that the dysregulated pathways identified in the seizure-associated module may be involved in the aetiology and maintenance of absence seizure activity. This dysregulated activity could potentially be modulated by targeting one or both central regulatory hubs.

Network Preservation Analysis Reveals Dysregulated Synaptic Modules and Regulatory Hubs Shared Between Alzheimer's Disease and Temporal Lobe Epilepsy.

Background: There is increased prevalence of epilepsy in patients with Alzheimer's disease (AD). Although shared pathological and clinical features have been identified, the underlying pathophysiology and cause-effect relationships are poorly understood. We aimed to identify commonly dysregulated groups of genes between these two disorders. Methods: Using publicly available transcriptomic data from hippocampal tissue of patients with temporal lobe epilepsy (TLE), late onset AD and non-AD controls, we constructed gene coexpression networks representing all three states. We then employed network preservation statistics to compare the density and connectivity-based preservation of functional gene modules between TLE, AD and controls and used the difference in significance scores as a surrogate quantifier of module preservation. Results: The majority (>90%) of functional gene modules were highly preserved between all coexpression networks, however several modules identified in the TLE network showed various degrees of preservation in the AD network compared to that of control. Of note, two synaptic signalling-associated modules and two metabolic modules showed substantial gain of preservation, while myelination and immune system-associated modules showed significant loss of preservation. The genes SCN3B and EPHA4 were identified as central regulatory hubs of the highly preserved synaptic signalling-associated module. GABRB3 and SCN2A were identified as central regulatory hubs of a smaller neurogenesis-associated module, which was enriched for multiple epileptic activity and seizure-related human phenotype ontologies. Conclusion: We conclude that these hubs and their downstream signalling pathways are common modulators of synaptic activity in the setting of AD and TLE, and may play a critical role in epileptogenesis in AD.

Altered metabolic pathways in a transgenic mouse model suggest mechanistic role of amyloid precursor protein overexpression in Alzheimer's disease.

INTRODUCTION: The mechanistic role of amyloid precursor protein (APP) in Alzheimer's disease (AD) remains unclear. OBJECTIVES: Here, we aimed to identify alterations in cerebral metabolites and metabolic pathways in cortex, hippocampus and serum samples from Tg2576 mice, a widely used mouse model of AD. METHODS: Metabolomic profilings using liquid chromatography-mass spectrometry were performed and analysed with MetaboAnalyst and weighted correlation network analysis (WGCNA). RESULTS: Expressions of 11 metabolites in cortex, including hydroxyphenyllactate-linked to oxidative stress-and phosphatidylserine-lipid metabolism-were significantly different between Tg2576 and WT mice (false discovery rate < 0.05). Four metabolic pathways from cortex, including glycerophospholipid metabolism and pyrimidine metabolism, and one pathway (sulphur metabolism) from hippocampus, were significantly enriched in Tg2576 mice. Network analysis identified five pathways, including alanine, aspartate and glutamate metabolism, and mitochondria electron transport chain, that were significantly correlated with AD genotype. CONCLUSIONS: Changes in metabolite concentrations and metabolic pathways are present in the early stage of APP pathology, and may be important for AD development and progression.

Persistence of neuronal representations through time and damage in the hippocampus.

How do neurons encode long-term memories? Bilateral imaging of neuronal activity in the mouse hippocampus reveals that, from one day to the next, ~40% of neurons change their responsiveness to cues, but thereafter only 1% of cells change per day. Despite these changes, neuronal responses are resilient to a lack of exposure to a previously completed task or to hippocampus lesions. Unlike individual neurons, the responses of which change after a few days, groups of neurons with inter- and intrahemispheric synchronous activity show stable responses for several weeks. The likelihood that a neuron maintains its responsiveness across days is proportional to the number of neurons with which its activity is synchronous. Information stored in individual neurons is relatively labile, but it can be reliably stored in networks of synchronously active neurons.

Regulation of chromatin folding by conformational variations of nucleosome linker DNA.

Linker DNA conformational variability has been proposed to direct nucleosome array folding into more or less compact chromatin fibers but direct experimental evidence for such models are lacking. Here, we tested this hypothesis by designing nucleosome arrays with A-tracts at specific locations in the nucleosome linkers to induce inward (AT-IN) and outward (AT-OUT) bending of the linker DNA. Using electron microscopy and analytical centrifugation techniques, we observed spontaneous folding of AT-IN nucleosome arrays into highly compact structures, comparable to those induced by linker histone H1. In contrast, AT-OUT nucleosome arrays formed less compact structures with decreased nucleosome interactions similar to wild-type nucleosome arrays. Adding linker histone H1 further increased compaction of the A-tract arrays while maintaining structural differences between them. Furthermore, restriction nuclease digestion revealed a strongly reduced accessibility of nucleosome linkers in the compact AT-IN arrays. Electron microscopy analysis and 3D computational Monte Carlo simulations are consistent with a profound zigzag linker DNA configuration and closer nucleosome proximity in the AT-IN arrays due to inward linker DNA bending. We propose that the evolutionary preferred positioning of A-tracts in DNA linkers may control chromatin higher-order folding and thus influence cellular processes such as gene expression, transcription and DNA repair.

Real-Time Gait Event Detection Based on Kinematic Data Coupled to a Biomechanical Model.

Real-time detection of multiple stance events, more specifically initial contact (IC), foot flat (FF), heel off (HO), and toe off (TO), could greatly benefit neurorobotic (NR) and neuroprosthetic (NP) control. Three real-time threshold-based algorithms have been developed, detecting the aforementioned events based on kinematic data in combination with a biomechanical model. Data from seven subjects walking at three speeds on an instrumented treadmill were used to validate the presented algorithms, accumulating to a total of 558 steps. The reference for the gait events was obtained using marker and force plate data. All algorithms had excellent precision and no false positives were observed. Timing delays of the presented algorithms were similar to current state-of-the-art algorithms for the detection of IC and TO, whereas smaller delays were achieved for the detection of FF. Our results indicate that, based on their high precision and low delays, these algorithms can be used for the control of an NR/NP, with the exception of the HO event. Kinematic data is used in most NR/NP control schemes and is thus available at no additional cost, resulting in a minimal computational burden. The presented methods can also be applied for screening pathological gait or gait analysis in general in/outside of the laboratory.