Two polygenic mouse models of major depressive disorders identify TMEM161B as a potential biomarker of disease in humans.

Treatments are only partially effective in major depressive disorders (MDD) but no biomarker exists to predict symptom improvement in patients. Animal models are essential tools in the development of antidepressant medications, but while recent genetic studies have demonstrated the polygenic contribution to MDD, current models are limited to either mimic the effect of a single gene or environmental factor. We developed in the past a model of depressive-like behaviors in mice (H/Rouen), using selective breeding based on behavioral reaction after an acute mild stress in the tail suspension test. Here, we propose a new mouse model of depression (H-TST) generated from a more complex genetic background and based on the same selection process. We first demonstrated that H/Rouen and H-TST mice had similar phenotypes and were more sensitive to glutamate-related antidepressant medications than selective serotonin reuptake inhibitors. We then conducted an exome sequencing on the two mouse models and showed that they had damaging variants in 174 identical genes, which have also been associated with MDD in humans. Among these genes, we showed a higher expression level of Tmem161b in brain and blood of our two mouse models. Changes in TMEM161B expression level was also observed in blood of MDD patients when compared with controls, and after 8-week treatment with duloxetine, mainly in good responders to treatment. Altogether, our results introduce H/Rouen and H-TST as the two first polygenic animal models of MDD and demonstrate their ability to identify biomarkers of the disease and to develop rapid and effective antidepressant medications.

Effects of the T-type calcium channel CaV3.2 R1584P mutation on absence seizure susceptibility in GAERS and NEC congenic rats models.

RATIONALE: Low-voltage-activated or T-type Ca2+ channels play a key role in the generation of seizures in absence epilepsy. We have described a homozygous, gain of function substitution mutation (R1584P) in the CaV3.2 T-type Ca2+ channel gene (Cacna1h) in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The non-epileptic control (NEC) rats, derived from the same original Wistar strains as GAERS but selectively in-breed not to express seizures, are null for the R1584P mutation. To study the effects of this mutation in rats who otherwise have a GAERS or NEC genetic background, we bred congenic GAERS-Cacna1hNEC (GAERS null for R1584P mutation) and congenic NEC-Cacna1hGAERS (NEC homozygous for R1584P mutation) and evaluated the seizure and behavioral phenotype of these strains in comparison to the original GAERS and NEC strains. METHODS: To evaluate seizure expression in the congenic strains, EEG electrodes were implanted in NEC, GAERS, GAERS-Cacna1hNEC without the R1584P mutation, and NEC-Cacna1hGAERS with the R1584P mutation rats. In the first study, continuous EEG recordings were acquired from week 4 (when seizures begin to develop in GAERS) to week 14 of age (when GAERS display hundreds of seizures per day). In the second study, the seizure and behavioral phenotype of GAERS and NEC-Cacna1hGAERS strains were evaluated during young age (6 weeks of age) and adulthood (16 weeks of age) of GAERS, NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The Open field test (OFT) and sucrose preference test (SPT) were performed to evaluate anxiety-like and depressive-like behavior, respectively. This was followed by EEG recordings at 18 weeks of age to quantify the seizures, and spike-wave discharge (SWD) cycle frequency. At the end of the study, the whole thalamus was collected for T-type calcium channel mRNA expression analysis. RESULTS: GAERS had a significantly shorter latency to first seizures and an increased number of seizures per day compared to GAERS-Cacna1hNEC. On the other hand, the presence of the R1584P mutation in the NEC-Cacna1hGAERS was not enough to generate spontaneous seizures in their seizure-resistant background. 6 and 16-week-old GAERS and GAERS-Cacna1hNEC rats showed anxiety-like behavior in the OFT, in contrast to NEC and NEC-Cacna1hGAERS. Results from the SPT showed that the GAERS developed depressive-like in the SPT compared to GAERS-Cacna1hNEC, NEC, and NEC-Cacna1hGAERS. Analysis of the EEG at 18 weeks of age showed that the GAERS had an increased number of seizures per day, increased total seizure duration and a higher cycle frequency of SWD relative to GAERS-Cacna1hNEC. However, the average seizure duration was not significantly different between strains. Quantitative real-time PCR showed that the T-type Ca2+ channel isoform CaV3.2 channel expression was significantly increased in GAERS compared to NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The presence of the R1584P mutation increased the total ratio of CaV3.2 + 25/-25 splice variants in GAERS and NEC-Cacna1hGAERS compared to NEC and GAERS-Cacna1hNEC. DISCUSSION: The data from this study demonstrate that the R1584P mutation in isolation on a seizure-resistant NEC genetic background was insufficient to generate absence seizures, and that a GAERS genetic background can cause seizures even without the mutation. However, the study provides evidence that the R1584P mutation acts as a modulator of seizures development and expression, and depressive-like behavior in the SPT, but not the anxiety phenotype of the GAERS model of absence epilepsy.

Enzyme assisted juice extraction from Dacryodes macrophylla as a potential bio-resource for wine production.

Atom fruit (Dacryodes macrophylla) is a Non-timber Forest Product (NTFP) that comprises a large seed, thick pulp, and a thin hard outer covering. The structural component of its cell wall and thick pulp make it difficult in extracting the juice. Also, Dacryodes macrophylla fruit is greatly underutilized, therefore the need to process and transform it into other value-added products. This work aims to enzymatically extract juice from Dacryodes macrophylla fruit with the aid of pectinase, ferment and test the acceptability of wine produced from this extract. The enzyme and non-enzyme treatments were carried out under the same conditions and their physicochemical properties such as pH, juice yield, total soluble solids, and Vitamin C were compared. A central composite design was used for the optimization of the processing factors for the enzyme extraction process. Enzyme treatment had a great impact on the juice yield (%) and Total soluble solids (TSS) (0Brix) of samples as it was as high as 81 ± 0.7% and 10.6 ± 0.02 0Brix whereas, that of the non-enzyme treatments were 46 ± 0.7% and 9.5 ± 0.02 0Brix respectively. However, the Vitamin C content of enzyme-treated juice decreased to 11.32 ± 0.13 mg/ml as compared to that of the non-enzyme-treated juice sample (15.7 ± 0.04 mg/ml). The optimum processing condition in the extraction of juice from the atom fruit was 1.84% enzyme concentration, 49.02 Ö¯C Incubation temperature, and 43.58 min Incubation time. During wine processing within 14 days of primary fermentation, the pH of the must decreased from 3.42 ± 0.07 to 3.26 ± 0.07 whereas the Titratable acidity (TA) increased from 0.16 ± 0.05 to 0.51 ± 0.0. The wine produced from Dacryodes macrophylla fruit showed promising results as its sensorial scores for all attributes including color, clarity, flavor, mouthfeel, alcoholic burn after taste and overall acceptability were all above 5. Thus, enzymes can be used to improve the juice yield of Dacryodes macrophylla fruit and hence, can be a potential bioresource for wine production.

Respiratory dysfunction in two rodent models of chronic epilepsy and acute seizures and its link with the brainstem serotonin system.

Patients with drug-resistant epilepsy can experience respiratory alterations, notably during seizures. The mechanisms underlying long-term alterations in respiratory function remain unclear. As the brainstem 5-HT system is a prominent modulator of respiratory function, this study aimed at determining whether epilepsy is associated with alterations in both the respiratory function and brainstem serotonin (5-HT) system in rats. Epilepsy was triggered by pilocarpine-induced status epilepticus in rats. Our results showed that 30-50% of epileptic (EPI) rats exhibited a sharp decrease in oxygen consumption (SDOC), low metabolic rate of oxygen, and slow regular ventilation (EPI/SDOC + rats). These alterations were detected only in rats with chronic epilepsy, independent of behavioral seizures, were persistent over time, and not associated with death. In these rats, 5-HT fiber density in the nucleus tractus solitarius was lower than that in the control and EPI/SDOC- rats. Both EPI/SDOC + rats and DBA/2 mice that present with audiogenic-induced seizure followed by fatal respiratory arrest-a model of sudden and expected death in epilepsy-had increased transcript levels of tryptophan hydroxylase 2 and 5-HT presynaptic transporter. Thus, our data support that 5-HT alterations are associated with chronic and acute epilepsy-related respiratory dysfunction.

Assessment of the Use of Multi-Channel Organic Electrodes to Record ENG on Small Nerves: Application to Phrenic Nerve Burst Detection.

Effective closed-loop neuromodulation relies on the acquisition of appropriate physiological control variables and the delivery of an appropriate stimulation signal. In particular, electroneurogram (ENG) data acquired from a set of electrodes applied at the surface of the nerve may be used as a potential control variable in this field. Improved electrode technologies and data processing methods are clearly needed in this context. In this work, we evaluated a new electrode technology based on multichannel organic electrodes (OE) and applied a signal processing chain in order to detect respiratory-related bursts from the phrenic nerve. Phrenic ENG (pENG) were acquired from nine Long Evans rats in situ preparations. For each preparation, a 16-channel OE was applied around the phrenic nerve's surface and a suction electrode was applied to the cut end of the same nerve. The former electrode provided input multivariate pENG signals while the latter electrode provided the gold standard for data analysis. Correlations between OE signals and that from the gold standard were estimated. Signal to noise ratio (SNR) and ROC curves were built to quantify phrenic bursts detection performance. Correlation score showed the ability of the OE to record high-quality pENG. Our methods allowed good phrenic bursts detection. However, we failed to demonstrate a spatial selectivity from the multiple pENG recorded with our OE matrix. Altogether, our results suggest that highly flexible and biocompatible multi-channel electrode may represent an interesting alternative to metallic cuff electrodes to perform nerve bursts detection and/or closed-loop neuromodulation.

Development and characterization of a PLGA-HA composite material to fabricate 3D-printed scaffolds for bone tissue engineering.

Additive manufacturing is a rising field in bone tissue engineering. Additive fabrication offers reproducibility, high precision and rapid manufacture of custom patient-specific scaffolds. The development of appropriate composite materials for biomedical applications is critical to reach clinical application of these novel biomaterials. In this work, medical grade poly(lactic-co-glycolic) acid (PLGA) was mixed with hydroxyapatite nanoparticles (nHA) to fabricate 3D porous scaffolds by Fused Deposition Modeling. We have first confirmed that the composite material could be printed in a reproductive manner. Physical characterization demonstrated a low degradation of the material during manufacturing steps and an expected loading and homogeneous distribution of nHA. In vitro biodegradation of the scaffolds showed modifications of morphological and physicochemical properties over time. The composite scaffolds were biocompatible and high cell viability was observed in vitro, as well as a maintain of cell proliferation. As expected, the addition of nHA displayed a positive impact on osteodifferentiation in vitro. Furthermore, a limited inflammatory reaction was observed after subcutaneous implantation of the materials in the rat. Overall, this study suggests that this composite material is suitable for bone tissue engineering applications.

Synergistic interactions in dilute aqueous solutions between alginate and tropical vegetal hydrocolloids.

Encapsulation in alginate beads has always been limited by the leakage due to the too wide distribution of pore sizes. Mixing alginate with other polymers have sometimes reduced the problem. Hydrocolloids from seven tropical vegetal species (barks of Triumfetta cordifolia and Bridelia thermifolia, seeds of Irvingia gabonensis and Beilschmiedia obscura, and leaves of Ceratotheca sesamoides, Adansonia digitata and Corchorus olitorius) were screened for synergistic interactions with alginate in dilute aqueous solution. Mixtures with alginate were made at different volume proportions and deviations from the initial viscosity set at 1 were evaluated. In distilled water, the gums from T. cordifolia, B. obscura, C. sesamoides and C. olitorius presented synergies with alginate. In 2 mM calcium chloride, the seven gums showed positive synergy. Interactions are favored by gum flexibility and the presence of charges, although high charges reduced the interactions. Alginate fraction of maximum viscosity enhancement depends on the ability to conformational order of the gum. The measure by laser diffraction of alginate-gum particles sizes at different fractions showed that the cooperative interactions did not always involve the largest complexes formed in gums associations. The occurrence of these interactions predicts the formation of homogeneous mixed gels at higher polymer and calcium concentrations.

Audiogenic seizure as a model of sudden death in epilepsy: A comparative study between four inbred mouse strains from early life to adulthood.

OBJECTIVE: Mouse models of sudden unexpected death in epileptic patients (SUDEP) using audiogenic seizures (AGS) are valuable because death can occur following a sound-induced seizure in the absence of any pharmacologic or electric component. However, only a few strains of mice are AGS prone, and the vast majority of studies involve DBA/2 or DBA/1 inbred strains. With the goal of characterizing the variation of AGS susceptibility with age, and of offering a larger panel of mice available for AGS studies, we performed a comparative study of the variability in AGS responses. METHODS: The variation of AGS with age was determined in two classically used inbred strains of mice, DBA/2 and DBA/1, and two additional strains, BALB/c and 129/SvTer. As AGS-stimulated tonic seizures can be lethal or nonlethal, even in the same inbred strain, in a second experiment, we addressed whether there is an innate capacity to reproduce the same response after a tonic AGS, referred to as "determinism," in the DBA/2J, DBA/1J, and 129/SvTer mouse strains. RESULTS: Results show that the 129/SvTer mouse is a more versatile model of SUDEP due to its wider age range of susceptibility compared to the DBA/2J and DBA/1J mouse strains. In addition, we show that determinism is not consistently evident in DBA/2J and 129/SvTer strains after AGS. Hence, one cannot be certain that a lethal AGS will always be lethal in successive testing after resuscitation and vice versa in these two mouse strains. SIGNIFICANCE: These studies highlight the phenotypic variability of AGS in different mouse strains, show the value of an additional mouse strain, 129/SvTer, for studies using AGS, and thus provide valuable information for future studies of AGS and SUDEP.

Ensemble Learning of Convolutional Neural Network, Support Vector Machine, and Best Linear Unbiased Predictor for Brain Age Prediction: ARAMIS Contribution to the Predictive Analytics Competition 2019 Challenge.

We ranked third in the Predictive Analytics Competition (PAC) 2019 challenge by achieving a mean absolute error (MAE) of 3.33 years in predicting age from T1-weighted MRI brain images. Our approach combined seven algorithms that allow generating predictions when the number of features exceeds the number of observations, in particular, two versions of best linear unbiased predictor (BLUP), support vector machine (SVM), two shallow convolutional neural networks (CNNs), and the famous ResNet and Inception V1. Ensemble learning was derived from estimating weights via linear regression in a hold-out subset of the training sample. We further evaluated and identified factors that could influence prediction accuracy: choice of algorithm, ensemble learning, and features used as input/MRI image processing. Our prediction error was correlated with age, and absolute error was greater for older participants, suggesting to increase the training sample for this subgroup. Our results may be used to guide researchers to build age predictors on healthy individuals, which can be used in research and in the clinics as non-specific predictors of disease status.

COMP Report: A survey of radiation safety regulations for medical imaging x-ray equipment in Canada.

X-ray regulations and room design methodology vary widely across Canada. The Canadian Organization of Medical Physicists (COMP) conducted a survey in 2016/2017 to provide a useful snapshot of existing variations in rules and methodologies for human patient medical imaging facilities. Some jurisdictions no longer have radiation safety regulatory requirements and COMP is concerned that lack of regulatory oversight might erode safe practices. Harmonized standards will facilitate oversight that will ensure continued attention is given to public safety and to control workplace exposure. COMP encourages all Canadian jurisdictions to adopt the dose limits and constraints outlined in Health Canada Safety Code 35 with the codicil that the design standards be updated to those outlined in NCRP 147 and BIR 2012.

Publisher Correction: The effect of attention and working memory on the estimation of elapsed time.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Quantification of Neural Conduction Block on the Rat Sciatic Nerve based on EMG Response.

Neural conduction block performed by balanced-charge kilohertz frequency alternating currents (KHFAC) has been identified as a potential technique for therapy delivery in different clinical setups. The underlying mechanisms that contribute to this phenomenon have been studied through computational models and animal experiments. However, the optimal stimulation parameters to achieve axonal conduction block are difficult to define, since they depend on the species, the nerve being targeted, as well as the technical and experimental setup. This study proposes an experimental setup along with an original data processing approach for the quantification of the effectiveness of neural conduction block. Experiments were performed on the sciatic nerve of two Sprague-Dawley rats, by evaluating different groups of stimulation parameters with varying amplitudes and frequencies, ranging from 1 to 10 mA and from 2 to 10 kHz, respectively. Results suggest that the effectiveness of axonal conduction block strongly depends on the selection of the stimulation parameters. In this work, more effective blockages were achieved for frequencies around 4 kHz and within an approximate amplitude range of 2 to 8 mA.

PEDOT:PSS electrodes for acute experimental evaluation of vagus nerve stimulation on rodents.

The vagus nerve (VN) is involved in the autonomic regulation of many physiological systems (cardiovascular, respiratory, gastrointestinal, etc.) and its stimulation is already an approved therapy for refractory epilepsy and depression. Other pathologies are thought to be treatable through vagus nerve stimulation (VNS), such as heart failure, cardiac arrhythmia, inflammation or auto-immune diseases. However, the efficacy of the stimulation is not always optimal, partly due to the materials and the architecture of currently available electrodes. Standard electrodes, composed of metallic rings that stimulate the whole diameter of the nerve, are not adapted to experimentations involving spatial selectivity. Efficient and selective charge injection is usually difficult to achieve simultaneously, especially in experimental setups using rodents, due to the thin diameter of their VN. In this paper, we show that we can take advantage of the high charge injection property of conducting polymers to acutely stimulate the vagus nerve in rodents, using individual active electrodes with dimensions $725\,\,\mu \mathrm{m}\times \,450\,\,\mu\mathrm{m}$. A particular PEDOT:PSS architecture integrating 12 active electrodes is developed and applied to the VN of one rat. A closed-loop VNS system developed in our previous works is used to stimulate the VN while analyzing the heart rate response. Results show the feasibility of this kind of electrodes for acute VNS on rodents and open the path towards new experimentations focused on selective stimulation and recording.

Long-term negative impact of an inappropriate first antiepileptic medication on the efficacy of a second antiepileptic medication in mice.

Childhood absence epilepsy (CAE) is one of the most frequent epilepsies in infancy. The first-line recommended therapy for CAE is based on the prescription of the narrow-spectrum ethosuximide and the broad-spectrum valproic acid, which have similar efficacy in the first 12 months. Nevertheless, some antiepileptic drugs (AEDs) may worsen seizure duration and type in this syndrome. In line with this, we have encountered a case of identical twins with CAE and early exposure to different antiseizure drugs leading to divergent outcomes. From this, we hypothesized that the first AED to treat CAE may determine the long-term prognosis, especially in the developing brain, and that some situations leading to drug resistance may be explained by use of an inappropriate first AED. Therefore, we investigated this hypothesis by using a genetic mouse model of absence epilepsy (BS/Orl). Mice received a first appropriate or inappropriate AED followed by the same appropriate AED. Our data demonstrate that an inappropriate first AED has a negative impact on the long-term efficacy of a second appropriate AED. This work supports the necessity to effectively diagnose epileptic syndromes prior to medication use, particularly in children, in order to prevent the deleterious effects of an inappropriate initial AED.

The effect of attention and working memory on the estimation of elapsed time.

Psychological models of time perception involve attention and memory: while attention typically regulates the flow of events, memory maintains timed events or intervals. The precise, and possibly distinct, roles of attention and memory in time perception remain debated. In this behavioral study, we tested 48 participants in a prospective duration estimation task while they fully attended to time or performed a working memory (WM) task. We report that paying attention to time lengthened perceived duration in the range of seconds to minutes, whereas diverting attention away from time shortened perceived duration. The overestimation due to attending to time did not scale with durations. To the contrary, increasing WM load systematically decreased subjective duration and this effect scaled with durations. Herein, we discuss the dissociation between attention and WM in timing and scalar variability from the perspective of Bayesian models of time estimations.

A Bayesian Perspective on Accumulation in the Magnitude System.

Several theoretical and empirical work posit the existence of a common magnitude system in the brain. Such a proposal implies that manipulating stimuli in one magnitude dimension (e.g. duration in time) should interfere with the subjective estimation of another magnitude dimension (e.g. size in space). Here, we asked whether a generalized Bayesian magnitude estimation system would sample sensory evidence using a common, amodal prior. Two psychophysical experiments separately tested participants on their perception of duration, surface, and numerosity when the non-target magnitude dimensions and the rate of sensory evidence accumulation were manipulated. First, we found that duration estimation was resilient to changes in surface and numerosity, whereas lengthening (shortening) the duration yielded under- (over-) estimations of surface and numerosity. Second, the perception of surface and numerosity were affected by changes in the rate of sensory evidence accumulation, whereas duration was not. Our results suggest that a generalized magnitude system based on Bayesian computations would minimally necessitate multiple priors.

Antioxidant activities of essential oil of Bidens pilosa (Linn. Var. Radita) used for the preservation of food qualities in North Cameroon.

This study aimed to determine the total antioxidant capacity of the essential oil (EO) of leaves of Bidens pilosa (Linn. Var. Radita) used as protectant of stored grains in Northern Cameroon. EO was characterized by GC-FID, antioxidant activity (AA) was determined by combining: evaluation of radical-scavenging activity, reducing power (RP) and co-oxidation of ß-carotene methods. Tests were carried out on crude and stored EO kept for two weeks at 31.48 ± 2.88°C and 58.56 ± 6.78% relative humidity. These conditions are the same as those of grain storage. GC analyses enabled the identification of 27 compounds, representing around 97.57% of the total oil contents. The major constituents of the EO were α-pinene (14.7%), ε-caryophyllene (13.5), and ß-ocimene (12.8%). The AA of the crude and stored EO are proportional to the concentrations and time of exposition. Exposed at the day light, this EO inhibit 77.4-18.69% for the DPPH system, 59.55-19.14% for RP method and 91.88-21.8% for ß-carotene-linoleate model system, respectively, from crude and 15 days storage EO at 20 mg L(-1). For the EC50 values, ß-carotene method is excellent and in the decreasing order of DPPH method, PR with 2.52 mg L(-1), 2.77 mg L(-1) and 4.13 mg L(-1), respectively, for the crude oil. The ET50 were 1.59 days for the RP method and 2.88 days DPPH system and ß-carotene-linoleate model system at 20 mg L(-1). These results showed that the EO of B. pilosa leaves exhibits AA that might be an added value for this EO preventing stored products from pest attacks.

Structural and functional changes during epileptogenesis in the mouse model of medial temporal lobe epilepsy.

An important issue in epilepsy research is to understand the structural and functional modifications leading to chronic epilepsy, characterized by spontaneous recurrent seizures, after initial brain insult. To address this issue, we recorded and analyzed electroencephalography (EEG) and quantitative magnetic resonance imaging (MRI) data during epileptogenesis in the in vivo mouse model of Medial Temporal Lobe Epilepsy (MTLE, kainate). Besides, this model of epilepsy is a particular form of drug-resistant epilepsy. The results indicate that high-field (4.7T) MRI parameters (T2-weighted; T2-quantitative) allow to detect the gradual neuro-anatomical changes that occur during epileptogenesis while electrophysiological parameters (number and duration of Hippocampal Paroxysmal Discharges) allow to assess the dysfunctional changes through the quantification of epileptiform activity. We found a strong correlation between EEG-based markers (invasive recording) and MRI-based parameters (non-invasive) periodically computed over the `latent period' that spans over two weeks, on average. These results indicated that both structural and functional changes occur in the considered epilepsy model and are considered as biomarkers of the installation of epilepsy. Additionally, such structural and functional changes can also be observed in human temporal lobe epilepsy. Interestingly, MRI imaging parameters could be used to track early (day-7) structural changes (gliosis, cell loss) in the lesioned brain and to quantify the evolution of epileptogenesis after traumatic brain injury.

Seizure expression, behavior, and brain morphology differences in colonies of Genetic Absence Epilepsy Rats from Strasbourg.

OBJECTIVE: Originally derived from a Wistar rat strain, a proportion of which displayed spontaneous absence-type seizures, Genetic Absence Epilepsy Rats from Strasbourg (GAERS) represent the most widely utilized animal model of genetic generalized epilepsy. Here we compare the seizure, behavioral, and brain morphometric characteristics of four main GAERS colonies that are being actively studied internationally: two from Melbourne (MELB and STRAS-MELB), one from Grenoble (GREN), and one from Istanbul (ISTAN). METHODS: Electroencephalography (EEG) recordings, behavioral examinations, and structural magnetic resonance imaging (MRI) studies were conducted on GAERS and Non-Epileptic Control (NEC) rats to assess and compare the following: (1) characteristics of spike-and-wave discharges, (2) anxiety-like and depressive-like behaviors, and (3) MRI brain morphology of regions of interest. RESULTS: Seizure characteristics varied between the colonies, with MELB GAERS exhibiting the least severe epilepsy phenotype with respect to seizure frequency, and GREN GAERS exhibiting four times more seizures than MELB. MELB and STRAS-MELB colonies both displayed consistent anxiety and depressive-like behaviors relative to NEC. MELB and GREN GAERS showed similar changes in brain morphology, including increased whole brain volume and increased somatosensory cortical width. A previously identified mutation in the Cacna1h gene controlling the CaV 3.2 T-type calcium channel (R1584P) was present in all four GAERS colonies, but absent in all NEC rats. SIGNIFICANCE: This study demonstrates differences in epilepsy severity between GAERS colonies that were derived from the same original colony in Strasbourg. This multi-institute study highlights the potential impact of environmental conditions and/or genetic drift on the severity of epileptic and behavioral phenotypes in rodent models of epilepsy.

Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.

Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.