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© 2020 Díaz-Casado et al., In the funding statement, the grant number from the funder Spanish JCyL cofinanced with the European Union FEDER funds 2017 is listed incorrectly. The correct grant number is: SA070P17.

The present study aimed to investigate the behavioral and anticonvulsant effects of lamotrigine (LTG) on the genetic audiogenic seizure hamster (GASH:Sal), an animal model of audiogenic seizure that is in the validation process. To evaluate the efficiency of acute and chronic treatments with LTG, GASH:Sals were treated with LTG either acutely via intraperitoneal injection (5-20mg/kg) or chronically via oral administration (20-25mg/kg/day). Their behavior was assessed via neuroethological analysis, and the anticonvulsant effect of LTG was evaluated based on the appearance and the severity of seizures. The results showed that acute administration of LTG exerts an anticonvulsant effect at the lowest dose tested (5mg/kg) and that chronic oral LTG treatment exerts an anticonvulsant effect at a dose of 20-25mg/kg/day. Furthermore, LTG treatment induced a low rate of secondary adverse effects. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

article Purpose:Animalmodelsofaudiogenicepilepsyareusefultoolstounderstandthemechanismsunderlyinghuman reflex epilepsies. There is accumulating evidence regarding behavioral, anatomical, electrophysiological, and genetic substrates of audiogenic seizure strains, but there are still aspects concerning their neurochemical basis that remain to be elucidated. Previous studies have shown the involved of γ-amino butyric acid (GABA) in audiogenic seizures. The aim of our research was to clarify the role of the GABAergic system in the generation of epileptic seizures in the genetic audiogenic seizure-prone hamster (GASH:Sal) strain. Material and methods: We studied the K + /Cl � cotransporter KCC2 and β2-GABAA-type receptor (GABAAR) and β3-GABAAR subunit expressions in the GASH:Sal both at rest and after repeated sound-induced seizures in dif- ferent brain regions using the Western blot technique. We also sequenced the coding region for the KCC2 gene both in wild- type and GASH:Sal hamsters. Results: Lower expressionof KCC2protein wasfoundinGASH:Salwhencomparedwith controls atrest inseveral brain areas: hippocampus, cortex, cerebellum, hypothalamus, pons-medulla, and mesencephalon. Repeated in- duction of seizures caused a decrease in KCC2 protein content in the inferior colliculus and hippocampus and an increase in the pons-medulla. When compared to controls, the basal β2-GABAAR subunit in the GASH:Sal was overexpressed in the inferior colliculus, rest of the mesencephalon, and cerebellum, whereas basal β3 subunit levels were lower in the inferior colliculus and rest of the mesencephalon. Repeated seizures increased β2 both in the inferior colliculus and in the hypothalamus and β3 in the hypothalamus. No differences in the KCC2 gene-coding region were found between GASH:Sal and wild-type hamsters. Conclusions: These data indicate that GABAergic system functioning is impaired in the GASH:Sal strain, and repeated seizures seem to aggravate this dysfunction. These results have potential clinical relevance and support the validity of employing the GASH:Sal strain as a model to study the neurochemistry of genetic reflex epilepsy.

A complex scalar λ is said to be an extended eigenvalue for an operator A on a Hilbert space H if there is a non-zero operator X such that AX=λXA, and in that case, X is said to be an extended eigenoperator. It is shown that if a bilateral weighted shift has a non-unimodular extended eigenvalue then every extended eigenoperator for A is strictly lower triangular. Also, it is shown that the set of the extended eigenvalues for an injective bilateral weighted shift is either C∖D or C∖{0} or D‾∖{0}, or T, and some examples are constructed in order to show that each of the four shapes does happen. Further, it is shown that the set of the extended eigenvalues for an injective bilateral weighted shift with an even sequence of weights is either C\{0} or T, and that the set of the extended eigenvalues for an invertible bilateral weighted shift is T. Finally, a factorization result is provided for the extended eigenoperators corresponding to a unimodular extended eigenvalue of an injective bilateral weighted shift.

The serotonergic system in the brain plays a major role in mood and anxiety regulation when exposed to stress. The aim of the present study was to evaluate the effects of Sertraline administration in coping with stress using the behavioural paradigms of the acoustic startle reflex (ASR) and its prepulse inhibition (PPI) in both sexes. Wistar rats were divided into two groups: intact animals and exposed to restraint stress (RS) 3 times per day during 7 days, which were then subdivided into three other groups: injected with Sertraline (5 mg/kg/day) or the drug vehicle saline for 8 consecutive days, and non-injected. ASR and PPI values were analyzed along 4 sessions to determine behavioral changes. Upon it, we also determine the effects of acute immobilization stress analyzing physiological stress indicators in blood. Our data show sex differences in response to stress paradigms. RS affected more intensely males than females, disturbing the males’ growth and the long-term startle habituation that were not affected in females. PPI increased in the vehicle-injected animals when compared to baseline in both sexes, and Sertraline reversed more efficiently it in females. Moreover, despite both sexes exposed to stressful paradigms exhibited a significant increase in serum glutamic-oxaloacetic transaminase and lactate dehydrogenase enzymes when compared with intact controls, as well as leucopenia, some differences according to sex were found in the haemostatic response to stress. Notably, the repeated injections procedure disturbed the early response to stress, which Sertraline only attenuated in both sexes. Our data suggest that 8-day Sertraline administration is effective in reversing stress-induced changes in some physio-logical parameters, but insufficient to return immunological values to normality.

Epilepsy modeling is essential for understanding the basic mechanisms of the epileptic process. The Genetic Audiogenic Seizure Hamster (GASH:Sal) exhibits generalized tonic–clonic seizures of genetic origin in response to sound stimulation and is currently being validated as a reliable model of epilepsy. Here, we performed a pharmacological and neuroethological study using well-known and widely used antiepileptic drugs (AEDs), including phenobarbital (PB), valproic acid (VPA), and levetiracetam (LEV). The intraperitoneal administration of PB (5–20 mg/kg) and VPA (100–300 mg/kg) produced a dose-dependent decrease in GASH:Sal audiogenic seizure severity scores. The administration of LEV (30–100 mg/kg) did not produce a clear effect. Phenobarbital showed a short plasmatic life and had a high antiepileptic effect starting at 10 mg/kg that was accompanied by ataxia. Valproic acid acted only at high concentrations and was the AED with the most ataxic effects. Levetiracetam at all doses also produced sedation and ataxia side effects. We conclude that the GASH:Sal is a reliable genetic model of epilepsy suitable to evaluate AEDs.

Producción Científica, GASH:Sal hamster strain and the control Syrian hamsters. The GASH:Sal constitutes an experimental model of reflex epilepsy of audiogenic origin derived from an autosomal recessive disorder. Thus, the GASH:Sal exhibits generalized tonic–clonic seizures, characterized by a short latency period after auditory stimulation, followed by wild running, a convulsive phase, and finally stupor, with origin in the brainstem. The seizure profile of the GASH:Sal is similar to those exhibited by other models of inherited AGS susceptibility, which decreases after six months of age, but the proneness across generations is maintained. The GASH:Sal can be considered a reliable model of audiogenic seizures, suitable to investigate current antiepileptic pharmaceutical treatments as well as novel therapeutic drugs.

Summary The study was performed to characterize GASH:SAL audiogenic seizures as true epileptic activity based on electroencephalographic markers acquired with a wireless implanted radiotelemetry system. We analyzed cortical EEG patterns synchronized with video recordings of convulsive behavior of the GASH:Sal hamster following an acoustic stimulus. All GASH:Sal presented archetypal motor symptoms comparable to current animal models of generalized tonic–clonic epilepsy. Seizures consisted of an initial bout of wild running, followed by opisthotonus, tonic–clonic convulsions, tonic limb extension, and terminated in postictal depression. EEG patterns correlated with behavior and displayed phase appropriate spike–wave complexes, low-amplitude desynchronized activity, and high frequency large-amplitude peaks. Our results confirm that electroencephalographic profiles of the audiogenic seizures of the hamster GASH:Sal are parallel to EEG patterns of other animal models of generalized tonic–clonic seizures. Therefore, this animal may serve as an appropriate model for epilepsy research.

We have detected a high incidence of lymphomas in a colony of GASH:Sal Syrian golden hamsters (Mesocricetus auratus). This strain is characterised by its ability to present convulsive crises of audiogenic origin. Almost 16 % (90 males and 60 females) of the 975 animals were affected during a 5-year period by the development of a progressing lymphoid tumour and exhibited similar clinical profiles characterised by lethargy, anorexia, evident abdominal distension, and a rapid disease progression resulting in mortality within 1 to 2 weeks. A TaqMan® probe-based real-time PCR analysis of genomic DNA from different tissue samples of the affected animals revealed the presence of a DNA sequence encoding the hamster polyomavirus (HaPyV) VP1 capsid protein. Additionally, immunohistochemical analysis using HaPyV-VP1-specific monoclonal antibodies confirmed the presence of viral proteins in all hamster tumour tissues analysed within the colony. An indirect ELISA and western blot analysis confirmed the presence of antibodies against the VP1 capsid protein in sera, not only from affected and non-affected GASH:Sal hamsters but also from control hamsters from the same breeding area. The HaPyV genome that accumulated in tumour tissues typically contained deletions affecting the noncoding regulatory region and adjacent sequences coding for the N-terminal part of the capsid protein VP2.