1. Abib RT, Gaman A, Dargel AA, Tamouza R, Kapczinski F, Gottfried C, Leboyer M. {{Intracellular Pathogen Infections and Immune Response in Autism}}. {Neuroimmunomodulation}. 2018: 1-9.
BACKGROUND/AIMS: Perinatal exposure to infections during critical developmental periods is a promising area of study in autism spectrum disorder (ASD). Epidemiological data has highlighted this relationship, pointing out significant correlations between perinatal exposure to pathogens and the occurrence of ASD. The aim of this review is to critically examine the present state of the art on intracellular pathogenic infection during pregnancy and postnatally, pointing out possible correlations with the development of ASD. METHODS: We reviewed and collected studies concerning potential associations between intracellular pathogens like viral, bacterial, and parasite infection and the risk of ASD. RESULTS: We included 14 publications, considering bacterial and/or viral infection that demonstrated the potential to trigger ASD. Nine case-control studies were included and 5 of them reported an association between infections and ASD. One of the 2 cohorts investigated demonstrated that maternal infection increased the risk of ASD in the offspring. Three cross-sectional studies demonstrated that ASD patients presented with chronic infections and active neuroinflammatory processes. Most of the reports suggest inflammatory response as a common factor, and interleukin 6 appears to be a key-player in this process. CONCLUSION: The immune responses generated by organisms that cause perinatal maternal infection, i.e., bacteria, viruses, or parasites, have been associated with the development of autism in offspring. Physiological changes transmitted from the mother during chronic or acute inflammation should be further investigated so that modulatory preventive measures can be developed.
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2. Grace N, Johnson BP, Rinehart NJ, Enticott PG. {{Are Motor Control and Regulation Problems Part of the ASD Motor Profile? A Handwriting Study}}. {Developmental neuropsychology}. 2018: 1-14.
The primary aim of this study was to kinematically assess how children with autism spectrum disorder (ASD) plan and control their handwriting actions. Forty-three boys aged between 8 to 12 years were included in the present analysis; 23 with ASD and 20 typically developing (TD) controls. Sophisticated objective and quantifiable assessment of movement metrics and dynamics was applied across a series of basic cursive handwriting sequences. Children with ASD demonstrated atypical control of handwriting metrics and dynamics, as well as significantly greater neuromotor noise relative to age-matched peers. They also engaged in less regular monitoring and regulation of their movement during the handwriting task. This study provides new insights into the way children with ASD plan and sequence their handwriting movements. Overall, results revealed that even at a basic level, children with ASD appear to have a breakdown in their ability to control and regulate their handwriting movements. This has important implications for the school-aged child who constantly engages in handwriting tasks within the classroom environment and provides insight into possible directions for future intervention.
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3. Hlushchenko I, Khanal P, Abouelezz A, Paavilainen VO, Hotulainen P. {{ASD-Associated De Novo Mutations in Five Actin Regulators Show Both Shared and Distinct Defects in Dendritic Spines and Inhibitory Synapses in Cultured Hippocampal Neurons}}. {Frontiers in cellular neuroscience}. 2018; 12: 217.
Many actin cytoskeleton-regulating proteins control dendritic spine morphology and density, which are cellular features often altered in autism spectrum disorder (ASD). Recent studies using animal models show that autism-related behavior can be rescued by either manipulating actin regulators or by reversing dendritic spine density or morphology. Based on these studies, the actin cytoskeleton is a potential target pathway for developing new ASD treatments. Thus, it is important to understand how different ASD-associated actin regulators contribute to the regulation of dendritic spines and how ASD-associated mutations modulate this regulation. For this study, we selected five genes encoding different actin-regulating proteins and induced ASD-associated de novo missense mutations in these proteins. We assessed the functionality of the wild-type and mutated proteins by analyzing their subcellular localization, and by analyzing the dendritic spine phenotypes induced by the expression of these proteins. As the imbalance between excitation and inhibition has been suggested to have a central role in ASD, we additionally evaluated the density, size and subcellular localization of inhibitory synapses. Common for all the proteins studied was the enrichment in dendritic spines. ASD-associated mutations induced changes in the localization of alpha-actinin-4, which localized less to dendritic spines, and for SWAP-70 and SrGAP3, which localized more to dendritic spines. Among the wild-type proteins studied, only alpha-actinin-4 expression caused a significant change in dendritic spine morphology by increasing the mushroom spine density and decreasing thin spine density. We hypothesized that mutations associated with ASD shift dendritic spine morphology from mushroom to thin spines. An M554V mutation in alpha-actinin-4 (ACTN4) resulted in the expected shift in dendritic spine morphology by increasing the density of thin spines. In addition, we observed a trend toward higher thin spine density with mutations in myosin IXb and SWAP-70. Myosin IIb and myosin IXb expression increased the proportion of inhibitory synapses in spines. The expression of mutated myosin IIb (Y265C), SrGAP3 (E469K), and SWAP-70 (L544F) induced variable changes in inhibitory synapses.
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4. Hosie S, Malone DT, Liu S, Glass M, Adlard PA, Hannan AJ, Hill-Yardin EL. {{Altered Amygdala Excitation and CB1 Receptor Modulation of Aggressive Behavior in the Neuroligin-3(R451C) Mouse Model of Autism}}. {Frontiers in cellular neuroscience}. 2018; 12: 234.
Understanding neuronal mechanisms underlying aggression in patients with autism spectrum disorder (ASD) could lead to better treatments and prognosis. The Neuroligin-3 (NL3)(R451C) mouse model of ASD has a heightened aggressive phenotype, however the biological mechanisms underlying this behavior are unknown. It is well established that NL3(R451C) mice have imbalanced excitatory and inhibitory synaptic activity in the hippocampus and somatosensory cortex. The amygdala plays a role in modulating aggressive behavior, however potential changes in synaptic activity in this region have not previously been assessed in this model. We investigated whether aggressive behavior is robustly present in mice expressing the R451C mutation, following back-crossing onto a congenic background strain. Endocannabinoids influence social interaction and aggressive behavior, therefore we also studied the effects of cannabinoid receptor 1 (CB1) agonist on NL3(R451C) mice. We report that NL3(R451C) mice have increased amplitude of miniature excitatory postsynaptic currents (EPSCs) with a concomitant decrease in the amplitude of inhibitory postsynaptic currents (IPSCs) in the basolateral amygdala. Importantly, we demonstrated that NL3(R451C) mice bred on a C57Bl/6 background strain exhibit an aggressive phenotype. Following non-sedating doses (0.3 and 1.0 mg/kg) of the CB1 receptor agonist WIN55,212-2 (WIN), we observed a significant reduction in aggressive behavior in NL3(R451C) mice. These findings demonstrate altered synaptic activity in the basolateral amygdala and suggest that the NL3(R451C) mouse model is a useful preclinical tool to understand the role of CB1 receptor function in aggressive behavior.
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5. Kim JW, Hong JY, Bae SM. {{Microglia and Autism Spectrum Disorder: Overview of Current Evidence and Novel Immunomodulatory Treatment Options}}. {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}. 2018; 16(3): 246-52.
Autism spectrum disorder is a rapidly increasing heterogeneous neurodevelopmental syndrome, remarked by persistent deficit in social communication, and restricted, repetitive patterns of behavior and interest. Lately, maternal immune activation and micgroglial dysfunction in the developing brain have been gaining mounting evidence and leading to studies of various novel agents as potential treatment options. A few immunomodulatory treatment options-luteolin, minocycline, suramin, vitamin D, gut microbiota-are discussed in the current article, regarding the current understanding of their mechanisms and evidence for potential clinical use. More studies are warranted to understand their exact mechanisms of action and to verify efficacy and safety in human subjects.
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6. Krasovska V, Doering LC. {{Regulation of IL-6 Secretion by Astrocytes via TLR4 in the Fragile X Mouse Model}}. {Front Mol Neurosci}. 2018; 11: 272.
Fragile X syndrome (FXS) is identified by abnormal dendrite morphology and altered synaptic protein expression. Astrocyte secreted factors such as Tenascin C (TNC), may contribute to the synaptic changes, including maturation of the synapse. TNC is a known endogenous ligand of toll-like receptor 4 (TLR4) that has been shown to induce the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6). At the molecular level, elevated IL-6 promotes excitatory synapse formation and increases dendrite spine length. With these molecular changes linked to the phenotype of FXS, we examined the expression and the mechanism of the endogenous TLR4 activator TNC, and its downstream target IL-6 in astrocytes from the Fragile X Mental Retardation 1 (FMR1) knockout (KO) mouse model. Secreted TNC and IL-6 were significantly increased in FMR1 KO astrocytes. Addition of TNC and lipopolysaccharide (LPS) induced IL-6 secretion, whereas the antagonist of TLR4 (LPS-RS) had an opposing effect. Cortical protein expression of TNC and IL-6 were also significantly elevated in the postnatal FMR1 KO mouse. In addition, there was an increase in the number of vesicular glutamate transporter 1 (VGLUT1)/post synaptic density protein 95 (PSD95) positive synaptic puncta of both wild-type (WT) and FMR1 KO neurons when plated with astrocyte conditioned media (ACM) from FMR1 KO astrocytes, compared to those plated with media from wild type astrocytes. By assessing the cellular mechanisms involved, a novel therapeutic option could be made available to target abnormalities of synaptic function seen in FXS.
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7. Le Gall E, Iakimova G. {{[Social cognition in schizophrenia and autism spectrum disorder: Points of convergence and functional differences]}}. {L’Encephale}. 2018.
INTRODUCTION: Schizophrenia and autistic spectrum disorder (ASD) are two neurodevelopmental disorders that have different symptom presentations, ages of onset and developmental courses. Both schizophrenia and ASD are characterized by marked deficit in communication, social interactions, affects and emotions. Social cognitive impairments in ASD and schizophrenia were demonstrated separately in both disorders. It was reported that these impairments have direct relation with social deficits of both disorders. The apparent similarity between social cognition impairments in ASD and schizophrenia highlights questions about the existence of common or different neurocognitive mechanisms related to social dysfunctions. In order to examine these questions, the present article provides a comprehensive review of all published studies which directly compare individuals with ASD and schizophrenia on the same cognitive tasks of social cognition. METHODS: The article search was made on Pubmed, PsycInfo and ScienceDirect, with the items: « autism », « Asperger syndrome », « schizophrenia », « social cognition », « theory of mind », « emotional processing », « social perception », « attributions style ». All published studies which compared individuals with ASD and schizophrenia, (diagnosed according to DSM-IV (APA, 1994) criteria and IQ>/=70), included control group were considered. The cognitive tasks were categorized according to four domains of social cognition defined by SCOPE (Pinkham et al., 2013): theory of mind (ToM), emotional processing (EP), social perception (SP) and attributional style/bias. The results were analyzed in terms of performances, cognitive profile and patterns of neural activations. Twenty-one published studies and two meta-analytic reviews were analyzed. RESULTS: Cognitive performance analysis confirms the convergence of abnormalities of people with autism and people with schizophrenia on 1st and 2nd order theory of mind, emotion processing and social perception. Quantitative results show reduced performance in ASD compared to SZ and Ct groups. Differences were observed between ASD and SZ regarding social situation comprehension, visual orientation and visuospatial exploration strategies, and attributional style highlighting different strategies on intentional process. Brain imaging studies show that people with autism present a reduced cerebral activity in several key regions of theory of mind (cingulate regions, superior temporal sulcus, paracentral lobule), and emotional treatment (primary and secondary somatosensory regions), while people with SZ exhibit an inappropriate increased activity in these regions. CONCLUSION: The present revue of the studies which directly compare individuals with ASD and schizophrenia on different domains of social cognition indicates that both disorders exhibit differences and similarities with regard to behavioral performances. Results in neuroimaging indicate different neurocognitive mechanisms underlie apparently similar social-cognitive impairments. Further studies are needed to better explore and describe divergent neurocognitive mechanisms in ASD and schizophrenia in order to provide treatment and remediation methods that take into account the specificities of neurocognitive processes in the two disorders.
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8. Li X, Cai E, Qin L, Kang J. {{[Abnormal electroencephalogram features extraction of autistic children based on wavelet transform combined with empirical modal decomposition]}}. {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi}. 2018; 35(4): 524-9.
Early detection and timely intervention are very essential for autism. This paper used the wavelet transform and empirical mode decomposition (EMD) to extract the features of electroencephalogram (EEG), to compare the feature differences of EEG between the autistic children and healthy children. The experimental subjects included 25 healthy children (aged 5-10 years old) and 25 children with autism (20 boys and 5 girls aged 5-10 years old) respectively. The alpha, beta, theta and delta rhythm wave spectra of the C3, C4, F3, F4, F7, F8, FP1, FP2, O1, O2, P3, P4, T3, T4, T5 and T6 channels were extracted and decomposed by EMD decomposition to obtain the intrinsic modal functions. Finally the support vector machine (SVM) classifier was used to implement assessment of autism and normal classification. The results showed that the accuracy could reach 87% and which was nearly 20% higher than that of the model combining the wavelet transform and sample entropy in the paper. Moreover, the accuracy of delta (1-4 Hz) rhythm wave was the highest among the four kinds of rhythms. And the classification accuracy of the forehead F7 channel, left FP1 channel and T6 channel in the temporal region were all up to 90%, which expressed the characteristics of EEG signals in autistic children better.
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9. Li X, Han X, Tu X, Zhu D, Feng Y, Jiang T, Yang Y, Qu J, Chen JG. {{An Autism-Related, Nonsense Foxp1 Mutant Induces Autophagy and Delays Radial Migration of the Cortical Neurons}}. {Cereb Cortex}. 2018.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that has a strong genetic component. Disruptions of FOXP1, a transcription factor expressed in the developing cerebral cortex, were associated with ASD. FOXP1(R525X) is a de novo heterozygous mutation found in patients with autism and severe mental retardation. To explore the neuronal basis of FOXP1(R525X) in ASD, we created Foxp1(R521X), a mouse homolog of the human variant. Ectopic expression of Foxp1(R521X) led to cytoplasmic aggregates and activated macroautophagy in neuroblastoma N2a cells and the developing neuronal cells. Cortical neurons expressing Foxp1(R521X) exhibited delayed migration and altered dendritic morphology. As a control, mutant Y435X that was expressed diffusively in the cytoplasm did not induce autophagy and migration delay in the cortex. The embryonic cortical cells had a minimal activity of nonsense-mediated mRNA decay (NMD) as assayed by a splicing-dependent NMD reporter. We hypothesize that the developing neuronal cells use autophagy but not NMD as a safeguard mechanism against nonsense mutant aggregates, resulting in impairment of the cortical development. This study suggests a novel mechanism other than heterozygous loss of FOXP1 for the development of ASD and may advance our understanding of the complex relationships between gene mutation and the related psychiatric disorders.
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10. Propper L. {{Managing disruptive behaviour in autism-spectrum disorder with guanfacine}}. {Journal of psychiatry & neuroscience : JPN}. 2018; 43(5): 359-60.
11. Rubenstein E, Young JC, Croen LA, DiGuiseppi C, Dowling NF, Lee LC, Schieve L, Wiggins LD, Daniels J. {{Brief Report: Maternal Opioid Prescription from Preconception Through Pregnancy and the Odds of Autism Spectrum Disorder and Autism Features in Children}}. {J Autism Dev Disord}. 2018.
Opioid use during pregnancy is associated with suboptimal pregnancy outcomes. Little is known about child neurodevelopmental outcomes. We examined associations between maternal opioid prescriptions preconception to delivery (peri-pregnancy) and child’s risk of ASD, developmental delay/disorder (DD) with no ASD features, or ASD/DD with autism features in the Study to Explore Early Development, a case-control study of neurodevelopment. Preconception opioid prescription was associated with 2.43 times the odds of ASD [95% confidence interval (CI) 0.99, 6.02] and 2.64 times the odds of ASD/DD with autism features (95% CI 1.10, 6.31) compared to mothers without prescriptions. Odds for ASD and ASD/DD were non-significantly elevated for first trimester prescriptions. Work exploring mechanisms and timing between peri-pregnancy opioid use and child neurodevelopment is needed.
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12. Wang Y, Zeng C, Li J, Zhou Z, Ju X, Xia S, Li Y, Liu A, Teng H, Zhang K, Shi L, Bi C, Xie W, He X, Jia Z, Jiang Y, Cai T, Wu J, Xia K, Sun ZS. {{PAK2 Haploinsufficiency Results in Synaptic Cytoskeleton Impairment and Autism-Related Behavior}}. {Cell reports}. 2018; 24(8): 2029-41.
Synaptic cytoskeleton dysfunction represents a common pathogenesis in neurodevelopmental disorders, such as autism spectrum disorder (ASD). The serine/threonine kinase PAK2 is a critical regulator of cytoskeleton dynamics. However, its function within the central nervous system and its role in ASD pathogenesis remain undefined. Here, we found that Pak2 haploinsufficiency resulted in markedly decreased synapse densities, defective long-term potentiation, and autism-related behaviors in mice. Phosphorylation levels of key actin regulators LIMK1 and cofilin, together with their mediated actin polymerization, were reduced in Pak2(+/-)mice. We identified one de novo PAK2 nonsense mutation that impaired PAK2 function in vitro and in vivo and four de novo copy-number deletions containing PAK2 in large cohorts of patients with ASD. PAK2 deficiency extensively perturbed functional networks associated with ASD by regulating actin cytoskeleton dynamics. Our genetic and functional results demonstrate a critical role of PAK2 in brain development and autism pathogenesis.
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13. Wiggins LD, Rubenstein E, Daniels J, DiGuiseppi C, Yeargin-Allsopp M, Schieve LA, Tian LH, Sabourin K, Moody E, Pinto-Martin J, Reyes N, Levy SE. {{A Phenotype of Childhood Autism Is Associated with Preexisting Maternal Anxiety and Depression}}. {Journal of abnormal child psychology}. 2018.
This study explored whether ASD phenotypes in the child were associated with a history of anxiety or depression in the mother. We hypothesized that an ASD profile in children characterized by mild delays and increased rates of dysregulation would be associated with preexisting maternal anxiety or depression. Participants were 672 preschool children with ASD and their mothers. Children were classified as ASD after a comprehensive developmental evaluation. Mothers reported whether a healthcare provider ever diagnosed them with anxiety or depression before the birth of their child. Four child ASD phenotypes were derived from latent class analysis: Mild Language Delay with Cognitive Rigidity (Type 1), Significant Developmental Delay with Repetitive Motor Behaviors (Type 2), General Developmental Delay (Type 3), and Mild Language and Motor Delay with Dysregulation (i.e., aggression, anxiety, depression, emotional reactivity, inattention, somatic complaints, and sleep problems) (Type 4). Type 2 ASD served as the referent category in statistical analyses. Results showed that 22.6% of mothers reported a diagnosis of anxiety or depression before the birth of their child. Maternal anxiety or depression was associated with 2.7 times the odds (95% confidence interval: 1.4, 5.3) of Type 4 or Dysregulated ASD in the child; maternal anxiety and depression was associated with 4.4 times the odds (95% confidence interval: 1.4, 14.0) of Type 4 or Dysregulated ASD in the child. Our findings suggest an association between Dysregulated ASD in the child and anxiety and depression in the mother. These findings can enhance screening methods and inform future research efforts.
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14. Xie W, Ge X, Li L, Yao A, Wang X, Li M, Gong X, Chu Z, Lu Z, Huang X, Jiao Y, Wang Y, Xiao M, Chen H, Xiang W, Yao P. {{Resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation}}. {Mol Autism}. 2018; 9: 43.
Background: Recent literatures indicate that maternal hormone exposure is a risk factor for autism spectrum disorder (ASD). We hypothesize that prenatal progestin exposure may counteract the neuroprotective effect of estrogen and contribute to ASD development, and we aim to develop a method to ameliorate prenatal progestin exposure-induced autism-like behavior. Methods: Experiment 1: Prenatal progestin exposure-induced offspring are treated with resveratrol (RSV) through either prenatal or postnatal exposure and then used for autism-like behavior testing and other biomedical analyses. Experiment 2: Prenatal norethindrone (NET) exposure-induced offspring are treated with ERbeta knockdown lentivirus together with RSV for further testing. Experiment 3: Pregnant dams are treated with prenatal NET exposure together with RSV, and the offspring are used for further testing. Results: Eight kinds of clinically relevant progestins were used for prenatal exposure in pregnant dams, and the offspring showed decreased ERbeta expression in the amygdala with autism-like behavior. Oral administration of either postnatal or prenatal RSV treatment significantly reversed this effect with ERbeta activation and ameliorated autism-like behavior. Further investigation showed that RSV activates ERbeta and its target genes by demethylation of DNA and histone on the ERbeta promoter, and then minimizes progestin-induced oxidative stress as well as the dysfunction of mitochondria and lipid metabolism in the brain, subsequently ameliorating autism-like behavior. Conclusions: We conclude that resveratrol ameliorates prenatal progestin exposure-induced autism-like behavior through ERbeta activation. Our data suggest that prenatal progestin exposure is a strong risk factor for autism-like behavior. Many potential clinical progestin applications, including oral contraceptive pills, preterm birth drugs, and progestin-contaminated drinking water or seafood, may be risk factors for ASD. In addition, RSV may be a good candidate for clinically rescuing or preventing ASD symptoms in humans, while high doses of resveratrol used in the animals may be a potential limitation for human application.
