Pubmed du 18/11/19

lundi 18 novembre 2019

1. Aabed K, Bhat RS, Al-Dbass A, Moubayed N, Algahtani N, Merghani NM, Alanazi A, Zayed N, El-Ansary A. Bee pollen and propolis improve neuroinflammation and dysbiosis induced by propionic acid, a short chain fatty acid in a rodent model of autism. Lipids Health Dis ;2019 (Nov 16) ;18(1):200.

BACKGROUND : Neuroinflammation plays a major role in the pathogenesis of autism because the cytokine levels are typically disturbed in the brain in autistic patients. Prebiotics-rich diet maintains the healthy gut microbiota and hence can regulate the neuroinflammation indirectly. The study aimed to investigate the role of bee pollen and propolis in ameliorating neuroinflammation, including cytokine levels, in an animal model of autism. METHODS : Hamsters were classified as four groups : Group I, control ; Group II, autistic model/animals treated with 250 mg propionic acid (PPA)/kg body weight (BW)/day for 3 days ; Group III, animals treated with bee pollen at a dose of 250 mg/kg BW/day for 4 weeks ; and Group IV, animals treated with propolis at a dose of 250 mg/kg BW/day for 4 weeks. Neuroinflammatory responses were evaluated using the levels of interferon gamma (IFN-gamma), interleukin 1 alpha (IL-1alpha), IL-6, IL-10, IL-12 (p70), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNFalpha). RESULTS : Significant decrease of IL-10 (P<0.026), VEGF (P<0.005), and TNFalpha(P<0.005) levels and increased IL-1alpha (P<0.032), IL-6(P<0.028), and IFN-gamma (P<0.013) levels were observed between the four studied groups. The neurotoxic effects of PPA was clearly presented as much higher IL-6, as pro-inflammatory cytokine (P<0.05), concomitant with much lower IL-10, as anti-inflammatory cytokine(P<0.015) compared to controls. Both bee pollen and propolis were effective in ameliorating the neurotoxic effects of PPA demonstrating non-significant changes of IL-6 and IL-10 when compared to control healthy hamsters. CONCLUSIONS : Our findings indicate that both bee pollen and propolis protect against neuroinflammation in the rodent model of autism. However, further studies are needed to investigate the clinical benefits of prebiotics-rich diet in neurodevelopmental disorders, such as autism.

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2. Ben-Reuven L, Reiner O. Dynamics of cortical progenitors and production of subcerebral neurons are altered in embryos of a maternal inflammation model for autism. Mol Psychiatry ;2019 (Nov 18)

The broad impairments in cognitive and neurologic functioning found in Autism Spectrum Disorder (ASD) patients are thought to originate during early prenatal developmental stages. Indeed, postmortem and imaging studies in ASD patients detected white-matter abnormalities, as well as prefrontal and temporal cortex deficits, evident from early childhood. Here, we used Maternal Immune Activation (MIA), a mouse model for ASD, in which the offsprings exhibit Autistic-like behaviors as well as cortical abnormalities. However, the dynamics that influence the number and the identity of newly born cortical neurons following maternal inflammation remains unknown. Our study shows early changes in the duration of the S-phase of PAX6(+) progenitors, leading to an increased proportion of neurogenic divisions and a reciprocal decrease in the proliferative divisions. In two different time points of maternal inflammation, MIA resulted in an overproduction of CTIP2(+) cortical neurons, which remained overrepresented at the end of gestation and in postnatal mice. Interestingly, MIA-resistant IL6-KO mice did not exhibit these changes. Lastly, we propose that elevated levels of the transcription factor PAX6 following MIA supports the overproduction of CTIP2(+) neurons. Taken together, our data reveals a possible link between maternal immune activation and the excess of cortical neurons found in the cortex of ASD patients.

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3. Beversdorf DQ, Stevens HE, Margolis KG, Van de Water J. Prenatal stress and maternal immune dysregulation in autism spectrum disorders- potential points for intervention. Curr Pharm Des ;2019 (Nov 18)

BACKGROUND : Genetics are a major etiological contributor to autism spectrum disorder (ASD). Environmental factors, however, also appear to contribute. ASD pathophysiology due to gene x environment is also beginning to be explored. One reason to focus on environmental factors is that they may allow opportunities for intervention or prevention. METHODS AND RESULTS : Herein, we review two such factors that have been associated with a significant proportion of ASD risk, prenatal stress exposure and maternal immune dysregulation. Maternal stress susceptibility appears to interact with prenatal stress exposure to affect offspring neurodevelopment. We also explore how maternal stress may interact with the microbiome in the neurodevelopmental setting. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. This might also be interrelated with maternal stress exposure. Animal models have been developed to explore pathophysiology targeting each of these factors. CONCLUSIONS : We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, and we are beginning to explore potential mitigating factors. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential targets for prevention or intervention for this subset of environmental-associated ASD cases.

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4. Chun H, Leung C, Wen SW, McDonald J, Shin HH. Maternal exposure to air pollution and risk of autism in children : A systematic review and meta-analysis. Environ Pollut ;2019 (Sep 26):113307.

BACKGROUND : The number of children diagnosed with autism spectrum disorder (ASD) has been increasing. Previous studies suggested potential association between pregnancy air pollution exposure and ASD. This systematic review and meta-analysis is intended to summarize the association between maternal exposure to outdoor air pollution and ASD in children by trimester based on recent studies. METHODS : A systematic literature search in 3 databases (Medline, Embase, and Web of Science) was performed using subject headings related to ASD and air pollution since 2007. Eligible studies were screened and evaluated based on predetermined criteria. For meta-analyses, the studies were grouped by air pollutant and exposure time (prenatal period and trimesters). Within-group studies were standardized by log odds ratio (OR) and then combined by three meta-analysis methods : frequentist fixed and random effects models, and Bayesian random effects model. RESULTS : Initial search identified 1564 papers, of which 25 studies remained for final analysis after duplicates and ineligible studies were removed. Of the 25 studies, 13, 14, 12, and 7 studies investigated ASD in children associated with PM2.5, PM10, NO2, and ozone, respectively. The frequentist and Bayesian random effects models resulted in different statistical significance. For prenatal period, frequentist meta-analysis returned significant pooled ORs with 95% confidence intervals, 1.06(1.01,1.11) for PM2.5 and 1.02(1.01,1.04) for NO2, whereas Bayesian meta-analysis showed similar ORs with wider 95% posterior intervals, 1.06(1.00,1.13) for PM2.5 and 1.02(1.00,1.05) for NO2. Third trimester appeared to have higher pooled ORs for PM2.5, PM10, and ozone, but patterns in the time-varying associations over the trimester were inconsistent. CONCLUSIONS : For positive association between maternal exposure to ambient air pollution and ASD in children, there is some evidence for PM2.5, weak evidence for NO2 and little evidence for PM10 and ozone. However, patterns in associations over trimesters were inconsistent among studies and among air pollutants.

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5. Desai A, Foss-Feig JH, Naples AJ, Coffman M, Trevisan DA, McPartland JC. Autistic and alexithymic traits modulate distinct aspects of face perception. Brain Cogn ;2019 (Dec) ;137:103616.

BACKGROUND : Atypical face processing is a prominent feature of autism spectrum disorder (ASD) but is not universal and is subject to individual variability. This heterogeneity could be accounted for by reliable yet unidentified subgroups within the diverse population of individuals with ASD. Alexithymia, which is characterized by difficulties in emotion recognition and identification, serves as a potential grouping factor. Recent research demonstrates that emotion recognition impairments in ASD are predicted by its comorbidity with alexithymia. The current study assessed the relative influence of autistic versus alexithymic traits on neural indices of face and emotion perception. METHODS : Capitalizing upon the temporal sensitivity of event-related potentials (ERPs), it investigates the distinct contributions of alexithymic versus autistic traits at specific stages of emotional face processing in 27 typically developing adults (18 female). ERP components reflecting sequential stages of perceptual processing (P100, N170 and N250) were recorded in response to fear and neutral faces. RESULTS : The results indicated that autistic traits were associated with structural encoding of faces (N170), whereas alexithymic traits were associated with more complex emotion decoding (N250). CONCLUSIONS : These findings have important implications for deconstructing heterogeneity within ASD.

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6. Desaunay P, Postel C, Bensaber F, Gonneaud J, Baleyte JM, Anger M, Guenole F, Malvy J, Bonnet-Brilhault F, Eustache F, Desgranges B, Guillery-Girard B. Prospective Memory in Adolescents with Autism : A Preliminary Study of the Impact of Memory Load. Dev Neuropsychol ;2019 (Nov 18):1-11.

We evaluated event-based prospective memory (EBPM) in adolescents with Autism, varying the load of the to-be-performed intentions. We included measures of inhibition, working memory and binding. Results showed that increasing the retrospective memory load reduced performance in controls. In Autism, adolescents were impaired in the low load condition with normal performance for the ongoing task, with the reverse pattern in the high load condition. EBPM may be impacted in Autism due to difficulty to process ongoing and EBPM tasks simultaneously possibly because of restricted inhibitory control.

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7. Friedman LK, Kahen BA. Chronic subconvulsive activity during early postnatal life produces autistic behavior in the absence of neurotoxicity in the juvenile weanling period. Behav Brain Res ;2019 (Nov 18) ;374:112046.

The diagnosis of autism spectrum disorder (ASD) varies from very mild to severe social and cognitive impairments. We hypothesized that epigenetic subconvulsive activity in early postnatal life may contribute to the development of autistic behavior in a sex-related manner. Low doses of kainic acid (KA) (25-100mug) were administered to rat pups for 15 days beginning on postnatal (P) day 6 to chronically elevate neuronal activity. A battery of classical and novel behavioral tests was used, and sex differences were observed. Our novel open handling test revealed that ASD males nose poked more often and ASD females climbed and escaped more frequently with age. In the social interaction test, ASD males were less social than ASD females who were more anxious in handling and elevated plus maze (EPM) tasks. To evaluate group dynamics, sibling and non-sibling control and experimental animals explored 3 different shaped novel social environments. Control pups huddled quickly and more frequently in all environments whether they socialized with littermates or non-siblings compared to ASD groups. Non-sibling ASD pups were erratic and huddled in smaller groups. In the object recognition test, only ASD males spent less time with the novel object compared to control pups. Data suggest that chronic subconvulsive activity in early postnatal life leads to an ASD phenotype in the absence of cell death. Males were more susceptible to developing asocial behaviors and cognitive pathologies, whereas females were prone to higher levels of hyperactivity and anxiety, validating our postnatal ASD model apparent in the pre-juvenile period.

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8. Jurek L, Longuet Y, Baltazar M, Amestoy A, Schmitt V, Desmurget M, Geoffray MM. How did I get so late so soon ? A review of time processing and management in autism. Behav Brain Res ;2019 (Nov 18) ;374:112121.

While the definition of Autism Spectrum Disorder (ASD) does not include any explicit criteria concerning difficulties of time perception or management, there is growing evidence of atypical temporal perception in individuals with ASD. This review synthesizes the evidence and gaps of the current literature on time processing in ASD. After a brief overview of clinical findings and available assessment tools, we synthetize outcomes of studies evaluating time perception at second and infra-second level, and then, recent literature on the circadian timing system. Findings point that all levels of time processing are atypical in autism (i.e. millisecond, interval and circadian timing). We discuss how time perception abnormalities and ASD core symptoms might intertwine and offer a new perspective for future research on this topic. We advocate the need to systematically assess temporal perception in ASD, and to include these aspects in global functional assessments before intervention. Implementing early intervention techniques to remediate time perception alterations in children with ASD may substantially improve their developmental trajectory.

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9. Kreilaus F, Chesworth R, Eapen V, Clarke R, Karl T. First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder. Behav Brain Res ;2019 (Nov 18) ;374:112057.

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder, which shares some clinical features with Autism spectrum disorder (ASD). The genetic factors relevant to the development of both disorders are yet to be fully understood, however, some genetic association studies have identified inner mitochondrial membrane peptidase subunit 2 (IMMP2L) as a potential risk gene for both GTS and ASD. The impact of Immp2l deficiency on behavioural domains is currently unknown. A new genetic mouse model for Immp2l was developed. Adult heterozygous (HET) and homozygous (HOMO) Immp2l knockdown (Immp2l KD) mice of both sexes were compared to wild type-like (WT) littermates in the open field (OF), social interaction, novel object recognition, marble burying, and prepulse inhibition (PPI). The effect of acute dexamphetamine (2 mg/kg) on OF behaviour was also determined. OF locomotion was significantly higher in HET compared to HOMO male littermates. Male and female HOMO mice were much more sensitive to the locomotor-stimulating effects of dexamphetamine (DEX), whereas only HOMO males exhibited significant increased DEX-induced OF exploration compared to control groups. HOMO females failed to habituate to an acoustic startle stimulus. Furthermore, compared to HOMO females, HET females showed reduced social interaction, and a similar trend was seen in HET males. The Immp2l KD mouse model possesses moderate face validity for preclinical research into GTS and ASD, in particular as dysfunctional dopaminergic neurotransmission appears to be one mechanism leading to disease presentation. The sex-dependent differences observed in most findings reinforce the strong influence of sex in the pathophysiology of GTS and ASD.

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10. Medishetti R, Rani R, Kavati S, Mahilkar A, Akella V, Saxena U, Kulkarni P, Sevilimedu A. A DNAzyme based knockdown model for Fragile-X syndrome in zebrafish reveals a critical window for therapeutic intervention. J Pharmacol Toxicol Methods ;2019 (Nov 14):106656.

INTRODUCTION : FXS is the leading cause of intellectual disabilities in males and a major monogenic cause of ASD (Autism spectrum disorders). It occurs due to the loss of FMRP, whose role in early development is not well understood. In this study, we have used a novel DNAzyme based approach to create a larval model of FXS in zebrafish with specific focus on the early developmental window. METHODS : Fmr1specific DNAzymes were electroporated into embryos to create theknockdown. Changes in RNA and protein levels of FMRP and relevant biomarkers were measured in the 0-7dpf window. Behavioral tests to measure anxiety, cognitive impairments and irritability in the larvae were conducted at the 7dpf stage. Drug treatment was carried out at various time points in the 0-7dpf window to identify the critical window for pharmacological intervention. RESULTS : The DNAzyme based knockdown approach led to a significant knockdown of FMRP in the zebrafish embryos, accompanied by increased anxiety, irritability and cognitive impairments at 7dpf, thus creating a robust larval model of FXS. Treatment with the Mavoglurant was able to rescue the behavioral phenotypes in the FXS larvae, and found to be more efficacious in the 0-3dpf window. DISCUSSION : The results from this study have revealed that a) a DNAzyme based knockdown approach can be used to create robust larval zebrafish model of disease, in a high-throughput manner and b) optimal window for therapeutic intervention for FXS as well as other pediatric diseases with a monogenic cause can be identified using such a model.

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