Evaluation of spontaneous seizure activity, sex-dependent differences, behavioral comorbidities, and alterations in CA1 neuron firing properties in a mouse model of Dravet Syndrome

Dravet syndrome (DS) is a rare childhood epilepsy disorder resulting in spontaneous, recurrent seizures and behavioral co-morbidities. A successful drug screening model should recapitulate the phenotypes observed in a clinical setting. To facilitate the discovery and development of anti-seizure drugs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has continued to evaluate a mouse model of DS with a focus on evaluating behavioral phenotypes, spontaneous seizure activity, and sex-dependent differences. Scn1aA1783V/WT mice exhibited increased hyperactivity, thigmotaxis, and deficits in nest-building behavior. Ex-vivo brain slice electrophysiology experiments revealed increased excitability of hippocampal CA1 neurons specifically due to increased action potential firing frequency in response to brief depolarizations and decreased frequency of spontaneous GABAergic synaptic events. A video-EEG study revealed mice had on average, 1 seizure per day, with males seizing significantly more frequently than females. Increased proportion of seizure activity occurred during the dark phase of the light/dark cycle in both sexes. While clobazam, a drug commonly prescribed to patients with DS, had no effect on spontaneous seizure activity at the tested doses, the seizure history and frequency observed in this study aids in determining the sample sizes and experimental timeline needed for adequately powered preclinical drug studies. Overall, this study provides a broad description of the Scn1aA1783V/WT mouse and highlights the utility of this model in therapy discovery.

CDDO-Me Attenuates Astroglial Autophagy via Nrf2-, ERK1/2-SP1- and Src-CK2-PTEN-PI3K/AKT-Mediated Signaling Pathways in the Hippocampus of Chronic Epilepsy Rats

Clasmatodendrosis is an autophagic astroglial death showing extensive swollen cell bodies with vacuoles and disintegrated/beaded processes. This astroglial degeneration is closely relevant to the synchronous epileptiform discharges. However, the underlying molecular mechanisms and the roles of clasmatodendrosis in spontaneous seizure activity are still unknown. The 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me; RTA 402) is one of the activators for nuclear factor-erythroid 2-related factor 2 (Nrf2) that is a redox-sensitive transcription factor. In the present study, we explored the effects of CDDO-Me on clasmatodendrosis in chronic epilepsy rats, which could prevent epilepsy-related complications. In the present study, clasmatodendritic astrocytes showed reduced Nrf2 expression and its nuclear accumulation, which were restored by CDDO-Me. CDDO-Me also abrogated heat shock protein 25 (HSP25) upregulation in clasmatodendritic astrocytes by regulating extracellular signal-related kinases 1/2 (ERK1/2)-specificity protein 1 (SP1)- and Src-casein kinase 2 (CK2)-phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-phosphatidylinositol-3-kinase (PI3K)-AKT-glycogen synthase kinase 3β (GSK3β)-bax-interacting factor 1 (Bif-1)-mediated signaling pathways in chronic epilepsy rats. In addition, CDDO-Me ameliorated spontaneous seizure duration, but not seizure frequency and behavioral seizure severity. Therefore, our findings suggest that clasmatodendrosis may affect seizure duration in chronic epilepsy rats, and that CDDO-Me may attenuate autophagic astroglial degeneration by regulating various signaling pathways.

Erratum: Catala, A., et al. Is There a Profile of Spontaneous Seizure-Alert Pet Dogs? A Survey of French People with Epilepsy. Animals 2020, 10, 254

The authors wish to make the following corrections to this paper: [...]

Enrichment of Circular RNA Expression Deregulation at the Transition to Recurrent Spontaneous Seizures in Experimental Temporal Lobe Epilepsy

Mesial temporal lobe epilepsy (mTLE) is a common form of epilepsy and is characterized by recurrent spontaneous seizures originating from the temporal lobe. The majority of mTLE patients develop pharmacoresistance to available anti-epileptic drugs (AEDs) while exhibiting severe pathological changes that can include hippocampal atrophy, neuronal death, gliosis and chronic seizures. The molecular mechanisms leading to mTLE remain incompletely understood, but are known to include defects in post-transcriptional gene expression regulation, including in non-coding RNAs (ncRNAs). Circular RNAs (circRNAs) are a class of recently rediscovered ncRNAs with high levels of expression in the brain and proposed roles in diverse neuronal processes. To explore a potential role for circRNAs in epilepsy, RNA-sequencing (RNA-seq) was performed on hippocampal tissue from a rat perforant pathway stimulation (PPS) model of TLE at different post-stimulation time points. This analysis revealed 218 differentially expressed (DE) circRNAs. Remarkably, the majority of these circRNAs were changed at the time of the occurrence of the first spontaneous seizure (DOFS). The expression pattern of two circRNAs, circ_Arhgap4 and circ_Nav3, was further validated and linked to miR-6328 and miR-10b-3p target regulation, respectively. This is the first study to examine the regulation of circRNAs during the development of epilepsy. It reveals an intriguing link between circRNA deregulation and the transition of brain networks into the state of spontaneous seizure activity. Together, our results provide a molecular framework for further understanding the role and mechanism-of-action of circRNAs in TLE.

Social and Political Activity of Peasantry in 1905-1907

By the beginning of 1905, a crisis was impending in all spheres of Russian society. Agrarian problems caused by objective and subjective factors prompted the peasantry to declare their principled positions on solving agrarian problems. The period of 1905-1907 is a vivid example of the struggle of the driving independent force of the revolution, the peasantry, for carrying out an agrarian revolution. Goal: To study the social and political activity of the Russian peasantry in 1905-1907. During 1905-1907, Russia was unsettled by a tide of the social and political activity of the peasantry. The protests, which began in Poltava and Kharkiv Provinces, spread throughout the state and in a short time became uncontrollable by the authorities. Scholars give different figures for the total number of peasant unrests, but despite these differences, it is not difficult to determine that during 1905-1907 peasant unrests covered up to 50% of all European Russia in different periods of peasants� revolutionary activity. Manifestations of the social and political activity of the peasantry can be observed in early 1905 in the spontaneous seizure of landowners� estates, later the peasants started to pillage, plunder, damage agricultural implements, go on strikes, and cut down forests without permission. The manifestations of early 1905 did not become a novelty for Russian society, but 1905 � 1907 were a test for the power structures of the state. After all, the peasantry, although they still �believed in the tsar�, reacted to the unsystematic actions of the power in solving agrarian problems by radical actions and the large-scale protests.

PDI-Mediated Reduction of Disulfide Bond on PSD95 Increases Spontaneous Seizure Activity by Regulating NR2A–PSD95 Interaction in Epileptic Rats Independent of S-Nitrosylation

Postsynaptic density-95 (PSD95), a major scaffolding protein, is critical in coupling N-methyl-D-aspartate receptor (NMDAR) to cellular signaling networks in the central nervous system. A couple of cysteine residues in the N-terminus of PSD95 are potential sites for disulfide bonding, S-nitrosylation and/or palmitoylation. Protein disulfide isomerase (PDI) reduces disulfide bonds (S-S) to free thiol (-SH) on various proteins. However, the involvement of PDI in disulfide bond formation/S-nitrosylation of PSD95 and its role in epilepsy are still unknown. In the present study, acute seizure activity significantly increased the bindings of PDI to NR2A, but not to PSD95, while it decreased the NR2A–PSD95 binding. In addition, pilocarpine-induced seizures increased the amount of nitrosylated (SNO-) thiols, not total (free and SNO-) thiols, on PSD95. Unlike acute seizure, spontaneous seizing rats showed the increases in PDI–PSD95 binding, total- and SNO-thiol levels on PSD95, and NR2A–PSD95 interaction. PDI siRNA effectively reduced spontaneous seizure activity with decreases in total thiol level on PSD95 and NR2A–PSD95 association. These findings indicate that PDI-mediated reduction of disulfide-bond formations may facilitate the NR2A–PSD95 binding and contribute to spontaneous seizure generation in epileptic animals.

Is there a Profile of Spontaneous Seizure-Alert Pet Dogs? A Survey of French People with Epilepsy

Despite controversies and the lack of research, dogs are empirically selected and trained to perform as service dogs, in relation to the dogs’ and future owners’ characteristics. We assessed the characteristics of both humans and dogs in an unbiased population (not selected or trained) of spontaneous seizure-alert by pet dogs and investigated whether we could replicate previous findings. We addressed a self-reporting questionnaire to French people with epilepsy. We analyzed the general characteristics of the humans and pet dogs and their behaviors that could alert their owner before a seizure. In addition, we used the Monash Canine Personality Questionnaire refined to evaluate pet dogs’ personality through five different traits, and the Monash Dog-Owner Relationship scale to assess human–dog relationships. In line with previous reports, we found no particular factor, either pet-, people- or epilepsy-related that could be associated with the presence or absence of alert behaviors. Alert behaviors and circumstances were explored and three different alert patterns emerged. In terms of personality, seizure-alert pet dogs scored significantly higher than non-alerting dogs for the traits “Motivation” and “Training Focus” and lower for “Neuroticism”. The owner–dog bond score was significantly higher for seizure-alert dogs than for non-alerting dogs.

Anaesthetic complications and emergencies preparedness part 2: intraoperative and recovery period complications

This is a straightforward reference guide designed to assist in diagnosing and treating anaesthetic complications and emergency situations in the perioperative period. Each complication is presented with its risk factors, signs for recognition and differential diagnoses when indicated. Management is presented in a step-by-step manner. Whenever possible, advice on how to prevent these situations from occurring is also provided. This second part focuses on complications more commonly observed in the intraoperative and postoperative period. It includes common situations, such as spontaneous/seizure-like movement or agitation; rare but life-threatening emergencies, such as malignant hyperthermia; and postoperative conditions less recognised in veterinary medicine, such as nausea and severe pain. The complications are presented in alphabetic order in each section (intraoperative and postoperative periods) for easy, rapid consultation.

Quantifying epileptogenesis in rats with spontaneous and responsive brain state dynamics

There is a crucial need to identify biomarkers of epileptogenesis that will help predict later development of seizures. This work identifies two novel electrophysiological biomarkers that quantify epilepsy progression in a rat model of epileptogenesis. The long-term tetanus toxin rat model was used to show the development and remission of epilepsy over several weeks. We measured the response to periodic electrical stimulation and features of spontaneous seizure dynamics over several weeks. Both biomarkers showed dramatic changes during epileptogenesis. Electrically induced responses began to change several days before seizures began and continued to change until seizures resolved. These changes were consistent across animals and allowed development of an algorithm that could differentiate which animals would later develop epilepsy. Once seizures began, there was a progression of seizure dynamics that closely follows recent theoretical predictions, suggesting that the underlying brain state was changing over time. This research demonstrates that induced electrical responses and seizure onset dynamics are useful biomarkers to quantify dynamical changes in epileptogenesis. These tools hold promise for robust quantification of the underlying epileptogenicity and prediction of later development of seizures.