1. An KM, Ikeda T, Yoshimura Y, Hasegawa C, Saito DN, Kumazaki H, Hirosawa T, Minabe Y, Kikuchi M. {{Altered Gamma Oscillations during Motor Control in Children with Autism Spectrum Disorder}}. {J Neurosci}. 2018.
Autism is hypothesized to result in a cortical excitatory and inhibitory imbalance driven by inhibitory interneuron dysfunction, which is associated with the generation of gamma oscillations. On the other hand, impaired motor control has been widely reported in autism. However, no study has focused on the gamma oscillations during motor control in autism. In the present study, we investigated the motor-related gamma oscillations in autism using magnetoencephalography. Magnetoencephalographic signals were recorded from 14 right-handed human children with autism (5 female), aged 5–7 years, and age- and IQ-matched 15 typically developing children during a motor task using their right index finger. Consistent with previous studies, the autism group showed a significantly longer button response time and reduced amplitude of motor-evoked magnetic fields. We observed that the autism group exhibited a low peak frequency of motor-related gamma oscillations from the contralateral primary motor cortex, and these were associated with the severity of autism symptoms. The autism group showed a reduced power of motor-related gamma oscillations in the bilateral primary motor cortex. A linear discriminant analysis using the button response time and gamma oscillations showed a high classification performance (86.2% accuracy). The alterations of the gamma oscillations in autism might reflect the cortical excitatory and inhibitory imbalance. Our findings provide an important clue into the behavioral and neurophysiological alterations in autism and a potential biomarker for autism.SIGNIFICANCE STATEMENTCurrently, the diagnosis of autism has been based on behavioral assessments, and a crucial issue in the diagnosis of autism is to identify objective and quantifiable clinical biomarkers. A key hypothesis of the neurophysiology of autism is an excitatory and inhibitory imbalance in the brain, which is associated with the generation of gamma oscillations. On the other hand, motor deficits have also been widely reported in autism. This is the first study to demonstrate low motor performance and altered motor-related gamma oscillations in autism, reflecting a brain excitatory and inhibitory imbalance. Using these behavioral and neurophysiological parameters, we classified autism and control group with good accuracy. This work provides important information on behavioral and neurophysiological alterations in patients with autism.
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2. Arnett AB, Rhoads CL, Hoekzema K, Turner TN, Gerdts J, Wallace AS, Bedrosian-Sermone S, Eichler EE, Bernier RA. {{The autism spectrum phenotype in ADNP syndrome}}. {Autism Res}. 2018.
Pathogenic disruptions to the activity-dependent neuroprotector homeobox (ADNP) gene are among the most common heterozygous genetic mutations associated with autism spectrum disorders (ASDs). Individuals with ADNP disruptions share a constellation of medical and psychiatric features, including ASD, intellectual disability (ID), dysmorphic features, and hypotonia. However, the profile of ASD symptoms associated with ADNP may differ from that of individuals with another ASD-associated single gene disruption or with ASD without a known genetic cause. The current study examined the ASD phenotype in a sample of representative youth with ADNP disruptions. Participants (N = 116, ages 4-22 years) included a cohort with ADNP mutations (n = 11) and three comparison groups with either a mutation to CHD8 (n = 11), a mutation to another ASD-associated gene (other mutation; n = 53), or ASD with no known genetic etiology (idiopathic ASD; n = 41). As expected, individuals with ADNP disruptions had higher rates of ID but less severe social affect symptoms compared to the CHD8 and Idiopathic ASD groups. In addition, verbal intelligence explained more variance in social impairment in the ADNP group compared to CHD8, other mutation, and idiopathic ASD comparison groups. Restricted and repetitive behaviors in the ADNP group were characterized by high levels of stereotyped motor behaviors, whereas the idiopathic ASD group showed high levels of restricted interests. Taken together, these results underscore the role of ADNP in cognitive functioning and suggest that social impairments in ADNP syndrome are consistent with severity of verbal deficits. LAY SUMMARY: Disruptions to the ADNP gene (i.e., ADNP syndrome) have been associated with autism spectrum disorder (ASD). This article describes intellectual disability, mild social difficulties, and severe repetitive motor movements in a group of 11 youth with ADNP Syndrome. We found lower rates of ASD than previously reported. Verbal skills explained individual variability in social impairment. This pattern suggests that the ADNP gene is primarily associated with learning and memory, and level of social difficulties is consistent with level of verbal impairment.
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3. Banerjee A, Ifrim MF, Valdez AN, Raj N, Bassell GJ. {{Aberrant RNA translation in fragile X syndrome: From FMRP mechanisms to emerging therapeutic strategies}}. {Brain Res}. 2018; 1693(Pt A): 24-36.
Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of Fragile X syndrome (FXS). Excess signaling through group 1 metabotropic glutamate receptors is commonly observed in mouse models of FXS, which in part is attributed to dysregulated translation and downstream signaling. Considering the wide spectrum of cellular and physiologic functions that loss of FMRP can affect in general, it may be advantageous to pursue disease mechanism based treatments that directly target translational components or signaling factors that regulate protein synthesis. Various FMRP targets upstream and downstream of the translational machinery are therefore being investigated to further our understanding of the molecular mechanism of RNA and protein synthesis dysregulation in FXS as well as test their potential role as therapeutic interventions to alleviate FXS associated symptoms. In this review, we will broadly discuss recent advancements made towards understanding the role of FMRP in translation regulation, new pre-clinical animal models with FMRP targets located at different levels of the translational and signal transduction pathways for therapeutic intervention as well as future use of stem cells to model FXS associated phenotypes.
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4. Becerra-Culqui TA, Getahun D, Chiu V, Sy LS, Tseng HF. {{Prenatal Tetanus, Diphtheria, Acellular Pertussis Vaccination and Autism Spectrum Disorder}}. {Pediatrics}. 2018.
: media-1vid110.1542/5803567555001PEDS-VA_2018-0120Video Abstract BACKGROUND: Increasing vaccination of pregnant women makes it important to assess safety events potentially linked to prenatal vaccination. This study investigates the association between prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination and autism spectrum disorder (ASD) risk in offspring. METHODS: This is a retrospective cohort study of mother-child pairs with deliveries January 1, 2011 to December 31, 2014 at Kaiser Permanente Southern California hospitals. Maternal Tdap vaccination from pregnancy start to delivery date was obtained from electronic medical records. A diagnosis of ASD was obtained by using International Classification of Diseases, Ninth and Tenth Revision codes. Children were managed from birth to first ASD diagnosis, end of membership, or end of follow-up (June 30, 2017). Cox proportional hazards models estimated the unadjusted and adjusted hazard ratios (HRs) for the association between maternal Tdap vaccination and ASD, with inverse probability of treatment weighting to adjust for confounding. RESULTS: Women vaccinated were more likely to be Asian American or Pacific Islander, be nulliparous, have a higher education, receive influenza vaccination prenatally, and give birth at term. ASD was diagnosed in 1341 (1.6%) children, and the incidence rate was 3.78 per 1000 person years in the Tdap exposed and 4.05 per 1000 person years in the unexposed group (HR: 0.98, 95% confidence interval: 0.88-1.09). The inverse probability of treatment weighting-adjusted analyses revealed that prenatal Tdap vaccination was not associated with an increased ASD risk (HR: 0.85, 95% confidence interval: 0.77-0.95). CONCLUSIONS: Prenatal Tdap vaccination was not associated with an increased ASD risk. We support recommendations to vaccinate pregnant women to protect infants, who are at highest risk of death after pertussis infection.
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5. Brown HK, Ray JG, Liu N, Lunsky Y, Vigod SN. {{Rapid repeat pregnancy among women with intellectual and developmental disabilities: a population-based cohort study}}. {CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne}. 2018; 190(32): E949-e56.
BACKGROUND: Rapid repeat pregnancy within 12 months of a live birth is associated with adverse perinatal outcomes. We evaluated the risk for rapid repeat pregnancy among women with intellectual and developmental disabilities, with whom sharing of information about pregnancy planning and contraception may be inadequate. METHODS: We accessed population-based health administrative data for all women with an index live birth in Ontario, Canada, for the period 2002-2013. We used modified Poisson regression to compare relative risks (RRs) for a rapid repeat pregnancy within 12 months of the index live birth in women with and without intellectual and developmental disabilities, first adjusting for demographic factors and then additionally adjusting for social, health and health care disparities. RESULTS: We compared 2855 women with intellectual and developmental disabilities and 923 367 women without such disabilities. At the index live birth, women with intellectual and developmental disabilities were more likely to be younger than 25 years of age (46.8% v. 18.2%) and to be disadvantaged on each measure of social, health and health care disparities. These women had a higher rate of rapid repeat pregnancy than those without such disabilities (7.6% v. 3.9%; adjusted RR 1.34, 95% confidence interval [CI] 1.18-1.54, after controlling for demographic factors). This risk was attenuated upon further adjustment for social, health and health care disparities (adjusted RR 1.00, 95% CI 0.87-1.14). INTERPRETATION: Rapid repeat pregnancy, which was more common among women with intellectual and developmental disabilities, may be explained by social, health and health care disparities. To optimize reproductive health, multifactorial approaches to address the marginalization experienced by this population are likely needed.
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6. Cheng FY, Fleming JT, Chiang C. {{Bergmann glial Sonic hedgehog signaling activity is required for proper cerebellar cortical expansion and architecture}}. {Developmental biology}. 2018; 440(2): 152-66.
Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNC(YFP-CreER) line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNC(YFP-CreER); Smo(F/-) (Smo(CKO)) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in Smo(CKO) CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture.
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7. Cole EJ, Enticott PG, Oberman LM, Gwynette MF, Casanova MF, Jackson SLJ, Jannati A, McPartland JC, Naples AJ, Puts NAJ. {{The Potential of Repetitive Transcranial Magnetic Stimulation for Autism Spectrum Disorder: A Consensus Statement}}. {Biol Psychiatry}. 2018.
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8. Dickie EW, Ameis SH, Shahab S, Calarco N, Smith DE, Miranda D, Viviano JD, Voineskos AN. {{Personalized Intrinsic Network Topography Mapping and Functional Connectivity Deficits in Autism Spectrum Disorder}}. {Biol Psychiatry}. 2018; 84(4): 278-86.
BACKGROUND: Recent advances in techniques using functional magnetic resonance imaging data demonstrate individually specific variation in brain architecture in healthy individuals. To our knowledge, the effects of individually specific variation in complex brain disorders have not been previously reported. METHODS: We developed a novel approach (Personalized Intrinsic Network Topography, PINT) for localizing individually specific resting-state networks using conventional resting-state functional magnetic resonance imaging scans. Using cross-sectional data from participants with autism spectrum disorder (ASD; n = 393) and typically developing (TD) control participants (n = 496) across 15 sites, we tested: 1) effect of diagnosis and age on the variability of intrinsic network locations and 2) whether prior findings of functional connectivity differences in persons with ASD compared with TD persons remain after PINT application. RESULTS: We found greater variability in the spatial locations of resting-state networks within individuals with ASD compared with those in TD individuals. For TD persons, variability decreased from childhood into adulthood and increased in late life, following a U-shaped pattern that was not present in those with ASD. Comparison of intrinsic connectivity between groups revealed that the application of PINT decreased the number of hypoconnected regions in ASD. CONCLUSIONS: Our results provide a new framework for measuring altered brain functioning in neurodevelopmental disorders that may have implications for tracking developmental course, phenotypic heterogeneity, and ultimately treatment response. We underscore the importance of accounting for individual variation in the study of complex brain disorders.
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9. Fricano-Kugler CJ, Getz SA, Williams MR, Zurawel AA, DeSpenza T, Jr., Frazel PW, Li M, O’Malley AJ, Moen EL, Luikart BW. {{Nuclear Excluded Autism-Associated Phosphatase and Tensin Homolog Mutations Dysregulate Neuronal Growth}}. {Biol Psychiatry}. 2018; 84(4): 265-77.
BACKGROUND: Phosphatase and tensin homolog (PTEN) negatively regulates downstream protein kinase B signaling, resulting in decreased cellular growth and proliferation. PTEN is mutated in a subset of children with autism spectrum disorder (ASD); however, the mechanism by which specific point mutations alter PTEN function is largely unknown. Here, we assessed how ASD-associated single-nucleotide variations in PTEN (ASD-PTEN) affect function. METHODS: We used viral-mediated molecular substitution of human PTEN into Pten knockout mouse neurons and assessed neuronal morphology to determine the functional impact of ASD-PTEN. We employed molecular cloning to examine how PTEN’s stability, subcellular localization, and catalytic activity affect neuronal growth. RESULTS: We identified a set of ASD-PTEN mutations displaying altered lipid phosphatase function and subcellular localization. We demonstrated that wild-type PTEN can rescue the neuronal hypertrophy, while PTEN H93R, F241S, D252G, W274L, N276S, and D326N failed to rescue this hypertrophy. A subset of these mutations lacked nuclear localization, prompting us to examine the role of nuclear PTEN in regulating neuronal growth. We found that nuclear PTEN alone is sufficient to regulate soma size. Furthermore, forced localization of the D252G and W274L mutations into the nucleus partially restores regulation of soma size. CONCLUSIONS: ASD-PTEN mutations display decreased stability, catalytic activity, and/or altered subcellular localization. Mutations lacking nuclear localization uncover a novel mechanism whereby lipid phosphatase activity in the nucleus can regulate mammalian target of rapamycin signaling and neuronal growth.
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10. Frye RE. {{Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents}}. {CNS drugs}. 2018.
Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.
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11. Glineburg MR, Todd PK, Charlet-Berguerand N, Sellier C. {{Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in Fragile X Tremor Ataxia Syndrome}}. {Brain Res}. 2018; 1693(Pt A): 43-54.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset inherited neurodegenerative disorder characterized by progressive intention tremor, gait ataxia and dementia associated with mild brain atrophy. The cause of FXTAS is a premutation expansion, of 55 to 200 CGG repeats localized within the 5’UTR of FMR1. These repeats are transcribed in the sense and antisense directions into mutants RNAs, which have increased expression in FXTAS. Furthermore, CGG sense and CCG antisense expanded repeats are translated into novel proteins despite their localization in putatively non-coding regions of the transcript. Here we focus on two proposed disease mechanisms for FXTAS: 1) RNA gain-of-function, whereby the mutant RNAs bind specific proteins and preclude their normal functions, and 2) repeat-associated non-AUG (RAN) translation, whereby translation through the CGG or CCG repeats leads to the production of toxic homopolypeptides, which in turn interfere with a variety of cellular functions. Here, we analyze the data generated to date on both of these potential molecular mechanisms and lay out a path forward for determining which factors drive FXTAS pathogenicity.
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12. Hacohen-Kleiman G, Sragovich S, Karmon G, Gao AYL, Grigg I, Pasmanik-Chor M, Le A, Korenkova V, McKinney RA, Gozes I. {{Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome}}. {The Journal of clinical investigation}. 2018.
Previous findings showed that in mice, complete knockout of activity-dependent neuroprotective protein (ADNP) abolishes brain formation, while haploinsufficiency (Adnp+/-) causes cognitive impairments. We hypothesized that mutations in ADNP lead to a developmental/autistic syndrome in children. Indeed, recent phenotypic characterization of children harboring ADNP mutations (ADNP syndrome children) revealed global developmental delays and intellectual disabilities, including speech and motor dysfunctions. Mechanistically, ADNP includes a SIP motif embedded in the ADNP-derived snippet, drug candidate NAP (NAPVSIPQ also known as CP201), which binds to microtubule end binding protein 3, essential for dendritic spine formation. Here, we established a unique neuronal membrane tagged green fluorescent protein expressing Adnp+/- mouse line allowing in vivo synaptic pathology quantification. We discovered that Adnp deficiency reduced dendritic spine density and altered synaptic gene expression, both of which were partly ameliorated by NAP treatment. Adnp+/- mice further exhibited global developmental delays, vocalization impediments, gait/motor dysfunctions and social/object memory impairments, all partially reversed by daily NAP administration (systemic/nasal). In conclusion, we now connected ADNP-related synaptic pathology to developmental/behavioral outcomes, establishing NAP in vivo target engagement and identifying potential biomarkers. Together, these studies pave the path toward clinical development of NAP (CP201) in the ADNP syndrome.
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13. Hassan WM, Al-Ayadhi L, Bjorklund G, Alabdali A, Chirumbolo S, El-Ansary A. {{The Use of Multi-parametric Biomarker Profiles May Increase the Accuracy of ASD Prediction}}. {Journal of molecular neuroscience : MN}. 2018.
Effective biomarkers are urgently needed to facilitate early diagnosis of autism spectrum disorder (ASD), permitting early intervention, and consequently improving prognosis. In this study, we evaluate the usefulness of nine biomarkers and their association (combination) in predicting ASD onset and development. Data were analyzed using multiple independent mathematical and statistical approaches to verify the suitability of obtained results as predictive parameters. All biomarkers tested appeared useful in predicting ASD, particularly vitamin E, glutathione-S-transferase, and dopamine. Combining biomarkers into profiles improved the accuracy of ASD prediction but still failed to distinguish between participants with severe versus mild or moderate ASD. Library-based identification was effective in predicting the occurrence of disease. Due to the small sample size and wide participant age variation in this study, we conclude that the use of multi-parametric biomarker profiles directly related to autism phenotype may help predict the disease occurrence more accurately, but studies using larger, more age-homogeneous populations are needed to corroborate our findings.
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14. Hicks SD, Uhlig R, Afshari P, Williams J, Chroneos M, Tierney-Aves C, Wagner K, Middleton FA. {{Oral microbiome activity in children with autism spectrum disorder}}. {Autism Res}. 2018.
Autism spectrum disorder (ASD) is associated with several oropharyngeal abnormalities, including buccal sensory sensitivity, taste and texture aversions, speech apraxia, and salivary transcriptome alterations. Furthermore, the oropharynx represents the sole entry point to the gastrointestinal (GI) tract. GI disturbances and alterations in the GI microbiome are established features of ASD, and may impact behavior through the « microbial-gut-brain axis. » Most studies of the ASD microbiome have used fecal samples. Here, we identified changes in the salivary microbiome of children aged 2-6 years across three developmental profiles: ASD (n = 180), nonautistic developmental delay (DD; n = 60), and typically developing (TD; n = 106) children. After RNA extraction and shotgun sequencing, actively transcribing taxa were quantified and tested for differences between groups and within ASD endophenotypes. A total of 12 taxa were altered between the developmental groups and 28 taxa were identified that distinguished ASD patients with and without GI disturbance, providing further evidence for the role of the gut-brain axis in ASD. Group classification accuracy was visualized with receiver operating characteristic curves and validated using a 50/50 hold-out procedure. Five microbial ratios distinguished ASD from TD participants (79.5% accuracy), three distinguished ASD from DD (76.5%), and three distinguished ASD children with/without GI disturbance (85.7%). Taxonomic pathways were assessed using the Kyoto Encyclopedia of Genes and Genomes microbial database and compared with one-way analysis of variance, revealing significant differences within energy metabolism and lysine degradation. Together, these results indicate that GI microbiome disruption in ASD extends to the oropharynx, and suggests oral microbiome profiling as a potential tool to evaluate ASD status. LAY SUMMARY: Previous research suggests that the bacteria living in the human gut may influence autistic behavior. This study examined genetic activity of microbes living in the mouth of over 300 children. The microbes with differences in children with autism were involved in energy processing and showed potential for identifying autism status.
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15. Hogeveen J, Krug MK, Elliott MV, Solomon M. {{Insula-Retrosplenial Cortex Overconnectivity Increases Internalizing via Reduced Insight in Autism}}. {Biol Psychiatry}. 2018; 84(4): 287-94.
BACKGROUND: Internalizing symptoms like anxiety and depression are common and impairing in autism spectrum disorder (ASD). Here, we test the hypothesis that aberrant functional connectivity among three brain networks (salience network [SN], default mode network [DMN], and frontoparietal network [FPN]) plays a role in the pathophysiology of internalizing in ASD. METHODS: We examined the association between resting-state functional connectivity and internalizing in 102 adolescents and young adults with ASD (n = 49) or typical development (n = 53). Seed-to-target functional connectivity was contrasted between adolescents and young adults with ASD and typically developing subjects using a recent parcellation of the human cerebral cortex, and connections that were aberrant in ASD were analyzed dimensionally as a function of parent-reported internalizing symptoms. RESULTS: Three connections demonstrated robust overconnectivity in ASD: 1) the anterior insula to the retrosplenial cortex (i.e., SN-DMN), 2) the anterior insula to the frontal pole (i.e., SN-FPN), and 3) the dorsolateral prefrontal cortex to the retrosplenial cortex (i.e., FPN-DMN). These differences remained significant after controlling for age, and no age-related effects survived correction. The SN-DMN connection was associated with greater internalizing in ASD, mediated by a bigger difference between self- and parent-reported internalizing. Control analyses found that the other two connections were not associated with internalizing, and SN-DMN connectivity was not associated with a well-matched control measure (externalizing symptoms). CONCLUSIONS: The present findings provide novel evidence for a specific link between SN-DMN overconnectivity and internalizing in ASD. Further, the mediation results suggest that intact anterior insula-retrosplenial connectivity may play a role in an individual’s generating insight into his or her own psychopathology.
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16. Jacquemont S, Pacini L, Jonch AE, Cencelli G, Rozenberg I, He Y, D’Andrea L, Pedini G, Eldeeb M, Willemsen R, Gasparini F, Tassone F, Hagerman R, Gomez-Mancilla B, Bagni C. {{Protein synthesis levels are increased in a subset of individuals with fragile X syndrome}}. {Hum Mol Genet}. 2018.
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17. Kopec AM, Fiorentino MR, Bilbo SD. {{Gut-immune-brain dysfunction in Autism: Importance of sex}}. {Brain Res}. 2018; 1693(Pt B): 214-7.
Autism Spectrum Disorder (ASD) is characterized by social behavior deficits, stereotypies, cognitive rigidity, and in some cases severe intellectual impairment and developmental delay. Although ASD is most widely identified by its neurological deficits, gastrointestinal issues are common in ASD. An intimate and complex relationship exists between the gut, the immune system, and the brain, leading to the hypothesis that ASD may be a systems-level disease affecting the gut and immune systems, in addition to the brain. Despite significant advances in understanding the contribution of the gut and immune systems to the etiology of ASD, there is an intriguing commonality among patients that is not well understood: they are predominantly male. Virtually no attention has been given to the potential role of sex-specific regulation of gut, peripheral, and central immune function in ASD, despite the 4:1 male-to-female bias in this disorder. In this review, we discuss recent revelations regarding the impact of gut-immune-brain relationships on social behavior in rodent models and in ASD patients, placing them in the context of known or putative sex specific mechanisms.
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18. Lee KY, Jewett KA, Chung HJ, Tsai NP. {{Loss of fragile X protein FMRP impairs homeostatic synaptic downscaling through tumor suppressor p53 and ubiquitin E3 ligase Nedd4-2}}. {Hum Mol Genet}. 2018; 27(16): 2805-16.
Synaptic scaling allows neurons to homeostatically readjust synaptic strength upon chronic neural activity perturbations. Although altered synaptic scaling has been implicated to underlie imbalanced brain excitability in neurological disorders such as autism spectrum disorders and epilepsy, the molecular dysregulation and restoration of synaptic scaling in those diseases have not been demonstrated. Here, we showed that the homeostatic synaptic downscaling is absent in the hippocampal neurons of Fmr1 KO mice, the mouse model of the most common inherited autism, fragile X syndrome (FXS). We found that the impaired homeostatic synaptic downscaling in Fmr1 KO neurons is caused by loss-of-function dephosphorylation of an epilepsy-associated ubiquitin E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2. Such dephosphorylation of Nedd4-2 is surprisingly caused by abnormally stable tumor suppressor p53 and subsequently destabilized kinase Akt. Dephosphorylated Nedd4-2 fails to elicit 14-3-3-dependent ubiquitination and down-regulation of the GluA1 subunit of AMPA receptor, and therefore impairs synaptic downscaling. Most importantly, using a pharmacological inhibitor of p53, Nedd4-2 phosphorylation, GluA1 ubiquitination and synaptic downscaling are all restored in Fmr1 KO neurons. Together, our results discover a novel cellular mechanism underlying synaptic downscaling, and demonstrate the dysregulation and successful restoration of this mechanism in the FXS mouse model.
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19. 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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20. Menon V. {{The Triple Network Model, Insight, and Large-Scale Brain Organization in Autism}}. {Biol Psychiatry}. 2018; 84(4): 236-8.
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21. Parras A, Anta H, Santos-Galindo M, Swarup V, Elorza A, Nieto-Gonzalez JL, Pico S, Hernandez IH, Diaz-Hernandez JI, Belloc E, Rodolosse A, Parikshak NN, Penagarikano O, Fernandez-Chacon R, Irimia M, Navarro P, Geschwind DH, Mendez R, Lucas JJ. {{Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing}}. {Nature}. 2018.
Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.
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22. Quartier A, Chatrousse L, Redin C, Keime C, Haumesser N, Maglott-Roth A, Brino L, Le Gras S, Benchoua A, Mandel JL, Piton A. {{Genes and Pathways Regulated by Androgens in Human Neural Cells, Potential Candidates for the Male Excess in Autism Spectrum Disorder}}. {Biol Psychiatry}. 2018; 84(4): 239-52.
BACKGROUND: Prenatal exposure to androgens during brain development in male individuals may participate to increase their susceptibility to develop neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability. However, little is known about the action of androgens in human neural cells. METHODS: We used human neural stem cells differentiated from embryonic stem cells to investigate targets of androgens. RESULTS: RNA sequencing revealed that treatment with dihydrotestosterone (DHT) leads to subtle but significant changes in the expression of about 200 genes, encoding proteins of extracellular matrix or involved in signal transduction of growth factors (e.g., insulin/insulin growth factor 1). We showed that the most differentially expressed genes (DEGs), RGCC, RNF144B, NRCAM, TRIM22, FAM107A, IGFBP5, and LAMA2, are reproducibly regulated by different androgens in different genetic backgrounds. We showed, by overexpressing the androgen receptor in neuroblastoma cells SH-SY5Y or knocking it down in human neural stem cells, that this regulation involves the androgen receptor. A chromatin immunoprecipitation combined with direct sequencing analysis identified androgen receptor-bound sequences in nearly half of the DHT-DEGs and in numerous other genes. DHT-DEGs appear enriched in genes involved in ASD (ASXL3, NLGN4X, etc.), associated with ASD (NRCAM), or differentially expressed in patients with ASD (FAM107A, IGFBP5). Androgens increase human neural stem cell proliferation and survival in nutrient-deprived culture conditions, with no detectable effect on regulation of neurite outgrowth. CONCLUSIONS: We characterized androgen action in neural progenitor cells, identifying DHT-DEGs that appear to be enriched in genes related to ASD. We also showed that androgens increase proliferation of neuronal precursors and protect them from death during their differentiation in nutrient-deprived conditions.
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23. Raspa M, Fitzgerald T, Furberg RD, Wylie A, Moultrie R, DeRamus M, Wheeler AC, McCormack L. {{Mobile technology use and skills among individuals with fragile X syndrome: implications for healthcare decision making}}. {J Intellect Disabil Res}. 2018.
BACKGROUND: Little is known about how individuals with fragile X syndrome (FXS) and their families use technology in daily life and what skills individuals with FXS can perform when using mobile technologies. METHODS: Using a mixed-methods design, including an online survey of parents (n = 198) and a skills assessment of individuals with FXS (n = 6), we examined the experiences and abilities of individuals with FXS for engaging with mobile technology. RESULTS: Parents reported that individuals with FXS often used technology in their daily lives, with variations based on age of child, sex, autism status, depression, and overall ability. Parents frequently sought and shared FXS-related information online. Assessment data revealed that individuals with FXS demonstrated proficiency in interacting with technology. CONCLUSIONS: Mobile technology is a tool that can be used in FXS to build skills and increase independence rather than simply for recreational purposes. Implications for using mobile technology to enhance healthcare decision making are discussed.
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24. Roux S, Lohof A, Ben-Ari Y, Poulain B, Bossu JL. {{Maturation of GABAergic Transmission in Cerebellar Purkinje Cells Is Sex Dependent and Altered in the Valproate Model of Autism}}. {Frontiers in cellular neuroscience}. 2018; 12: 232.
Brain development is accompanied by a shift in gamma-aminobutyric acid (GABA) response from depolarizing-excitatory to hyperpolarizing-inhibitory, due to a reduction of intracellular chloride concentration. This sequence is delayed in Autism Spectrum Disorders (ASD). We now report a similar alteration of this shift in the cerebellum, a structure implicated in ASD. Using single GABAA receptor channel recordings in cerebellar Purkinje cells (PCs), we found two conductance levels (18 and 10 pS), the former being dominant in newborns and the latter in young-adults. This conductance shift and the depolarizing/excitatory to hyperpolarizing/inhibitory GABA shift occurred 4 days later in females than males. Our data support a sex-dependent developmental shift of GABA conductance and chloride gradient, leading to different developmental timing in males and females. Because these developmental sequences are altered in ASD, this study further stresses the importance of developmental timing in pathological neurodevelopment.
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25. Vaccaro TDS, Sorrentino JM, Salvador S, Veit T, Souza DO, de Almeida RF. {{Alterations in the MicroRNA of the Blood of Autism Spectrum Disorder Patients: Effects on Epigenetic Regulation and Potential Biomarkers}}. {Behav Sci (Basel)}. 2018; 8(8).
Aims: Autism spectrum disorder (ASD) refers to a group of heterogeneous brain-based neurodevelopmental disorders with different levels of symptom severity. Given the challenges, the clinical diagnosis of ASD is based on information gained from interviews with patients’ parents. The heterogeneous pathogenesis of this disorder appears to be driven by genetic and environmental interactions, which also plays a vital role in predisposing individuals to ASD with different commitment levels. In recent years, it has been proposed that epigenetic modifications directly contribute to the pathogenesis of several neurodevelopmental disorders, such as ASD. The microRNAs (miRNAs) comprises a species of short noncoding RNA that regulate gene expression post-transcriptionally and have an essential functional role in the brain, particularly in neuronal plasticity and neuronal development, and could be involved in ASD pathophysiology. The aim of this study is to evaluate the expression of blood miRNA in correlation with clinical findings in patients with ASD, and to find possible biomarkers for the disorder. Results: From a total of 26 miRNA studied, seven were significantly altered in ASD patients, when compared to the control group: miR34c-5p, miR92a-2-5p, miR-145-5p and miR199a-5p were up-regulated and miR27a-3p, miR19-b-1-5p and miR193a-5p were down-regulated in ASD patients. Discussion: The main targets of these miRNAs are involved in immunological developmental, immune response and protein synthesis at transcriptional and translational levels. The up-regulation of both miR-199a-5p and miR92a-2a and down-regulation of miR-193a and miR-27a was observed in AD patients, and may in turn affect the SIRT1, HDAC2, and PI3K/Akt-TSC:mTOR signaling pathways. Furthermore, MeCP2 is a target of miR-199a-5p, and is involved in Rett Syndrome (RTT), which possibly explains the autistic phenotype in male patients with this syndrome.
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26. Vallee A, Vallee JN, Lecarpentier Y. {{PPARgamma agonists: potential treatment for autism spectrum disorder by inhibiting the canonical WNT/beta-catenin pathway}}. {Mol Psychiatry}. 2018.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by a deficit in social interactions and communication with repetitive and restrictive behavior. No curative treatments are available for ASD. Pharmacological treatments do not address the core ASD behaviors, but target comorbid symptoms. Dysregulation of the core neurodevelopmental pathways is associated with the clinical presentation of ASD, and the canonical WNT/beta-catenin pathway is one of the major pathways involved. The canonical WNT/beta-catenin pathway participates in the development of the central nervous system, and its dysregulation involves developmental cognitive disorders. In numerous tissues, the canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARgamma) act in an opposed manner. In ASD, the canonical WNT/beta-catenin pathway is increased while PPARgamma seems to be decreased. PPARgamma agonists present a beneficial effect in treatment for ASD children through their anti-inflammatory role. Moreover, they induce the inhibition of the canonical WNT/beta-catenin pathway in several pathophysiological states. We focus this review on the hypothesis of an opposed interplay between PPARgamma and the canonical WNT/beta-catenin pathway in ASD and the potential role of PPARgamma agonists as treatment for ASD.
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27. Wegiel J, Brown WT, La Fauci G, Adayev T, Kascsak R, Kascsak R, Flory M, Kaczmarski W, Kuchna I, Nowicki K, Martinez-Cerdeno V, Wisniewski T, Wegiel J. {{The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13)}}. {Autism Res}. 2018.
Fragile X syndrome (FXS), caused by lack of fragile X mental retardation protein (FMRP), is associated with a high prevalence of autism. The deficit of FMRP reported in idiopathic autism suggests a mechanistic overlap between FXS and autism. The overall goal of this study is to detect neuropathological commonalities of FMRP deficits in the brains of people with idiopathic autism and with syndromic autism caused by dup15q11.2-q13 (dup15). This study tests the hypothesis based on our preliminary data that both idiopathic and syndromic autism are associated with brain region-specific deficits of neuronal FMRP and structural changes of the affected neurons. This immunocytochemical study revealed neuronal FMRP deficits and shrinkage of deficient neurons in the cerebral cortex, subcortical structures, and cerebellum in subjects with idiopathic and dup(15)/autism. Neuronal FMRP deficit coexists with surprising infiltration of the brains of autistic children and adults with FMRP-positive astrocytes known to be typical only for the fetal and short postnatal periods. In the examined autistic subjects, these astrocytes selectively infiltrate the border between white and gray matter in the cerebral and cerebellar cortex, the molecular layer of the cortex, part of the amygdala and thalamus, central cerebellar white matter, and dentate nucleus. Astrocyte pathology results in an additional local loss of FMRP in neurons and their shrinkage. Neuronal deficit of FMRP and shrinkage of affected neurons in structures free of FMRP-positive astrocytes and regions infiltrated with FMRP-expressing astrocytes appear to reflect mechanistic, neuropathological, and functional commonalities of FMRP abnormalities in FXS and autism spectrum disorder. LAY SUMMARY: Immunocytochemistry reveals a deficit of fragile X mental retardation protein (FMRP) in neurons of cortical and subcortical brain structures but increased FMRP expression in astrocytes infiltrating gray and white matter. The detected shrinkage of FMRP-deficient neurons may provide a mechanistic explanation of reported neuronal structural and functional changes in autism. This study contributes to growing evidence of mechanistic commonalities between fragile X syndrome and autism spectrum disorder.
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28. Wu Y, Qi F, Song D, He Z, Zuo Z, Yang Y, Liu Q, Hu S, Wang X, Zheng X, Yang J, Yuan Q, Zou J, Guo K, Yao Z. {{Prenatal influenza vaccination rescues impairments of social behavior and lamination in a mouse model of autism}}. {J Neuroinflammation}. 2018; 15(1): 228.
BACKGROUND: Prenatal infection is a substantial risk factor for neurodevelopmental disorders such as autism in offspring. We have previously reported that influenza vaccination (VAC) during early pregnancy contributes to neurogenesis and behavioral function in offspring. RESULTS: Here, we probe the efficacy of VAC pretreatment on autism-like behaviors in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) mouse model. We show that VAC improves abnormal fetal brain cytoarchitecture and lamination, an effect associated with promotion of intermediate progenitor cell differentiation in MIA fetal brain. These beneficial effects are sufficient to prevent social deficits in adult MIA offspring. Furthermore, whole-genome analysis suggests a strong interaction between Ikzf1 (IKAROS family zinc-finger 1) and neuronal differentiation. Intriguingly, VAC rescues excessive microglial Ikzf1 expression and attenuates microglial inflammatory responses in the MIA fetal brain. CONCLUSIONS: Our study implies that a preprocessed influenza vaccination prevents maternal bacterial infection from causing neocortical lamination impairments and autism-related behaviors in offspring.
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29. Zhang F, Kang Y, Wang M, Li Y, Xu T, Yang W, Song H, Wu H, Shu Q, Jin P. {{Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets}}. {Hum Mol Genet}. 2018.
N6-methyladenosine (m6A) is the most prevalent internal modification of mammalian messenger RNAs (mRNAs) and long non-coding RNAs. The biological functions of this reversible RNA modification can be interpreted by cytoplasmic and nuclear « m6A reader » proteins to fine-tune gene expression, such as mRNA degradation and translation initiation. Here we profiled transcriptome-wide m6A sites in adult mouse cerebral cortex, underscoring that m6A is a widespread epitranscriptomic modification in brain. Interestingly, the mRNA targets of fragile X mental retardation protein (FMRP), a selective RNA-binding protein, are enriched for m6A marks. Loss of functional FMRP leads to Fragile X syndrome (FXS), the most common inherited form of intellectual disability. Transcriptome-wide gene expression profiling identified 2,035 genes differentially expressed in the absence of FMRP in cortex, and 92.5% of 174 downregulated FMRP targets are marked by m6A. Biochemical analyses indicate that FMRP binds to the m6A sites of its mRNA targets and interacts with m6A reader YTHDF2 in an RNA-independent manner. FMRP maintains the stability of its mRNA targets while YTHDF2 promotes the degradation of these mRNAs. These data together suggest that FMRP regulates the stability of its m6A-marked mRNA targets through YTHDF2, which could potentially contribute to the molecular pathogenesis of FXS.
