Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

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L’apport de la génétique à la compréhension des origines de l’autisme

Les progrès de la génétique, des neurosciences cognitives, des sciences de l’éducation, de l’imagerie cérébrale ont transformé la compréhension des origines et de la nature des troubles du spectre de l’autisme (TSA), appelés aussi troubles envahissants du développement (TED). En conséquence les pratiques recommandées pour l’accompagnement de ces personnes ont radicalement changé.À la découverte de l’autisme expose l’état actuel des connaissances scientifiques sur l’autisme, la situation des personnes avec autisme en France, ainsi que les recommandations de bonnes pratiques de la Haute autorité de santé (HAS) et quelques fondements de ces recommandations.Cet ouvrage est le fruit d’un travail collectif et s’adresse à un large public s’intéressant aux troubles du spectre de l’autisme : parents, enseignants, personnels soignants – mais aussi élus, et toute personne appelée à rencontrer, intervenir, ou organiser l’accompagnement de personnes avec autisme. Il rassemble, dans un langage simple, les points de vue de personnes avec autisme, de parents, de médecins, de professionnels médico-sociaux, de chercheurs et d’enseignants

DOES FETAL AND NEONATAL EXPOSURE TO ODOUR VARIETY AFFECT LATER RESPONSE TO NOVELTY IN MICE?

Vertebrate embryos and neonates are competent to encode odor information, and to later use it in guiding neonatal, juvenile, and, sometimes, adult behaviour. These data generally derive from experiments in which single odorants were administered. Here, we consider whether the perinatal exposure to multiple odorants administered sequentially will affect later behaviour. Mouse perinates were exposed to contrasted chemosensory regimen through the mother's ingestion of odorized water from days E15 through P21. The effects of 3 treatments were considered: 1/ olfactory monotony (MON; females accessing a benzaldehyde solution 5 days/week; n=46); 2/ olfactory variety (VAR; females accessing each other day solutions of benzaldehyde, vaniline, lyral, limonene, cineol; n=45); 3/ Control (CON; females receiving non-odorized water; n=46). At weaning (P21), all groups received a standard regimen. Treatment influence was assessed in measuring exploration behaviour in contexts involving chemosensory or visual novelty. On P23, all mice underwent an open field test, and then an episode of confrontation with a novel object. On P27, half of each group underwent a 24-hr 2-bottle choice test pairing water and an unfamiliar odorant (anethole), the other half undergoing a paired-odour choice opposing familiar and novel odorants (benzaldehyde vs. anethole). Perinatal odour exposure influenced the behaviour of the pups. In the open field test, CON mice spent less time than MON and VAR young mice (which were not differentiable) in the central area before to introduce the object and more time in the coins areas in the object presence. In the 2-bottle choice test, MON and VAR mice indistinctly drank more of the novel odorant than CON mice. Finally, in the paired-odour choice test, VAR pups stayed longer in the odorized areas than MON pups, and spent more time closer to the unfamiliar odour. In sum, this study confirmed that the perinatal manipulation of the odour environment positively influences pup responses to odours. It further reveals that perinatal exposure to odour variability has contrasted effects on pup responsiveness in contexts bearing chemosensory and visual novelty

BKCa Channel Opener Molecules as a new therapy in Fragile X Syndrome ?

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Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

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Dietary supplement enriched in antioxidants and omega-3 promotes glutamine synthesis in Müller cells: a key process against oxidative stress in retina

International audienceTo prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation

IMPLICATION D'UN GENE DU SPLICEOSOME DANS UN CAS DE DEFICIENCE MENTALE SEVERE ?

International audienceLa déficience mentale (DM) se définit par un quotient intellectuel inférieur à 70 associé à un déficit fonctionnel du comportement adaptatif apparu avant l'âge de 18 ans (American Psychiatric Association, 1994). Sa prévalence est estimée à 1-3% de la population mondiale et ses étiologies sont extrêmement hétérogènes. Cependant, 25 à 50% des DM sévères sont d'origine génétique. Les réarrangements chromosomiques équilibrés de novo sont associés à un risque croissant de DM ou de malformations congénitales, ce qui suggère que le phénotype observé est causé par la suppression, la perturbation ou l'inactivation d'un ou plusieurs gène(s) dans les régions des points de cassure. C'est grâce à l'étude de tels remaniements chromosomiques que de nombreux gènes de DM ont été identifiés. Nous rapportons ici l'analyse moléculaire de la translocation réciproque équilibrée [46, X, t (X; 3) (p22 ; q13)] de novo portée par une fillette qui présente une déficience mentale sévère et une dysmorphie faciale. Une étude par approche « whole genome sequencing » s'est révélée non informative, le point de cassure du chromosome 3 étant situé en territoire centromérique répété. L'analyse pangénomique par puce haute résolution Affymetrix (SNP6.0 GenomeWide Human) nous a permis d'exclure l'existence de remaniements chromosomiques significatifs pouvant être à l'origine du phénotype. L'analyse transcriptomique par puce Affymetrix (Human EXON1.0) objectivait la dérégulation de l'expression de nombreux gènes. Parmi ces gènes, la baisse du taux de transcrit de gènes de déficience mentale, tels que FMR1 (syndrome de l'X fragile), CRBN (DM héréditaire), MECP2 (Syndrome de Rett) ou encore KCNMA1 (DM et autisme) expliquent le phénotype DM de la fillette porteuse du remaniement. De plus, cinq gènes se trouvent sous-exprimés dans la région de point de cassure Xp22. Parmi eux, un gène code pour une sous-unité régulatrice du complexe permettant la transcription génique, le spliceosome. Les anomalies transcriptionnelles multiples observées résultent donc probablement de cette anomalie. Cependant, à ce jour nous sommes encore dans l'incapacité de choisir entre une anomalie primaire de ce gène, liée au point de cassure Xp22, ou une anomalie secondaire ayant pour conséquence une dérégulation transcriptionnelle entrainant une déficience mentale

Pre- and postnatal exposure to low dose glufosinate ammonium induces autism-like phenotypes in mice.

International audienceGlufosinate ammonium (GLA) is one of the most widely used herbicides in agriculture. As is the case for most pesticides, potential adverse effects of GLA have not been studied from the perspective of developmental neurotoxicity. Early pesticides exposure may weaken the basic structure of the developing brain and cause permanent changes leading to a wide range of lifelong effects on health and/or behavior. Here, we addressed the developmental impact of GLA by exposing female mice to low dose GLA during both pre- and postnatal periods and analyzed potential developmental and behavioral changes of the offspring during infancy and adulthood. A neurobehavioral test battery revealed significant effects of GLA maternal exposure on early reflex development, pup communication, affiliative behaviors, and preference for social olfactory cues, but emotional reactivity and emotional memory remained unaltered. These behavioral alterations showed a striking resemblance to changes seen in animal models of Autistic Spectrum Disorders. At the brain level, GLA maternal exposure caused some increase in relative brain weight of the offspring. In addition, reduced expression of Pten and Peg3 - two genes implicated in autism-like deficits - was observed in the brain of GLA-exposed pups at postnatal day 15. Our work thus provides new data on the link between pre- and postnatal exposure to the herbicide GLA and the onset of autism-like symptoms later in life. It also raises fundamental concerns about the ability of current safety testing to assess risks of pesticide exposure during critical developmental periods