1. Berto S, Treacher AH, Caglayan E, Luo D, Haney JR, Gandal MJ, Geschwind DH, Montillo AA, Konopka G. Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder. Nat Commun;2022 (Jun 9);13(1):3328.

Gene expression covaries with brain activity as measured by resting state functional magnetic resonance imaging (MRI). However, it is unclear how genomic differences driven by disease state can affect this relationship. Here, we integrate from the ABIDE I and II imaging cohorts with datasets of gene expression in brains of neurotypical individuals and individuals with autism spectrum disorder (ASD) with regionally matched brain activity measurements from fMRI datasets. We identify genes linked with brain activity whose association is disrupted in ASD. We identified a subset of genes that showed a differential developmental trajectory in individuals with ASD compared with controls. These genes are enriched in voltage-gated ion channels and inhibitory neurons, pointing to excitation-inhibition imbalance in ASD. We further assessed differences at the regional level showing that the primary visual cortex is the most affected region in ASD. Our results link disrupted brain expression patterns of individuals with ASD to brain activity and show developmental, cell type, and regional enrichment of activity linked genes.

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2. Bülow P, Segal M, Bassell GJ. Mechanisms Driving the Emergence of Neuronal Hyperexcitability in Fragile X Syndrome. Int J Mol Sci;2022 (Jun 5);23(11)

Hyperexcitability is a shared neurophysiological phenotype across various genetic neurodevelopmental disorders, including Fragile X syndrome (FXS). Several patient symptoms are associated with hyperexcitability, but a puzzling feature is that their onset is often delayed until their second and third year of life. It remains unclear how and why hyperexcitability emerges in neurodevelopmental disorders. FXS is caused by the loss of FMRP, an RNA-binding protein which has many critical roles including protein synthesis-dependent and independent regulation of ion channels and receptors, as well as global regulation of protein synthesis. Here, we discussed recent literature uncovering novel mechanisms that may drive the progressive onset of hyperexcitability in the FXS brain. We discussed in detail how recent publications have highlighted defects in homeostatic plasticity, providing new insight on the FXS brain and suggest pharmacotherapeutic strategies in FXS and other neurodevelopmental disorders.

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3. Byiers B. Integrated biopsychosocial pain research in intellectual and developmental disability. Dev Med Child Neurol;2022 (Jun 10)

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4. Chong PF, Torio M, Fujii F, Hirata Y, Matsuoka W, Sonoda Y, Ichimiya Y, Yada Y, Kaku N, Ishimura M, Sasazuki M, Koga Y, Sanefuji M, Sakai Y, Ohga S. Critical vitamin deficiencies in autism spectrum disorder: Reversible and irreversible outcomes. Eur J Clin Nutr;2022 (Jun 10)

Vitamin deficiencies are an emerging concern in the management of children with autism spectrum disorder (ASD). Particular attention is required for recognizing the variable signs caused by unbalanced food intakes. We herein report two patients with multiple vitamin deficiencies who needed critical care showing different prognoses. Patient 1 with ‘Shoshin’ beriberi presenting with cardiac arrest had thiamine deficiency developed severe neurological sequelae despite rapid vitamin supplementation. Patient 2, who had leg pain and a limping gait, showed a rapid recovery with intravenous infusion and tube feeding after being diagnosed with scurvy. A literature search revealed several children with ASD with critically ill thiamine deficiency, but few reports documented a life-threatening condition in the form of cardiac arrest at the onset. Considering the high observation rate of food selectivity in children with ASD, early intervention is required to prevent the exacerbation of vitamin deficiencies to severe neurological disabilities.

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5. Deserno MK, Bathelt J, Groenman AP, Geurts HM. Probing the overarching continuum theory: data-driven phenotypic clustering of children with ASD or ADHD. Eur Child Adolesc Psychiatry;2022 (Jun 10)

The clinical validity of the distinction between ADHD and ASD is a longstanding discussion. Recent advances in the realm of data-driven analytic techniques now enable us to formally investigate theories aiming to explain the frequent co-occurrence of these neurodevelopmental conditions. In this study, we probe different theoretical positions by means of a pre-registered integrative approach of novel classification, subgrouping, and taxometric techniques in a representative sample (N = 434), and replicate the results in an independent sample (N = 219) of children (ADHD, ASD, and typically developing) aged 7-14 years. First, Random Forest Classification could predict diagnostic groups based on questionnaire data with limited accuracy-suggesting some remaining overlap in behavioral symptoms between them. Second, community detection identified four distinct groups, but none of them showed a symptom profile clearly related to either ADHD or ASD in neither the original sample nor the replication sample. Third, taxometric analyses showed evidence for a categorical distinction between ASD and typically developing children, a dimensional characterization of the difference between ADHD and typically developing children, and mixed results for the distinction between the diagnostic groups. We present a novel framework of cutting-edge statistical techniques which represent recent advances in both the models and the data used for research in psychiatric nosology. Our results suggest that ASD and ADHD cannot be unambiguously characterized as either two separate clinical entities or opposite ends of a spectrum, and highlight the need to study ADHD and ASD traits in tandem.

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6. Dubreucq J, Martin A, Gabayet F, Plasse J, Wiesepape C, Quilès C, Verdoux H, Franck N, Lysaker PH. Contrasting the Social Cognitive and Metacognitive Capacities Among Patients With Schizophrenia and Autism Spectrum Disorders Enrolled in Psychiatric Rehabilitation. J Nerv Ment Dis;2022 (May 14)

Unique deficits in synthetic metacognition have been found in schizophrenia when compared with other psychiatric conditions and community controls. Although persons with autism spectrum disorders (ASD) display similar deficits in social cognition relative to those with schizophrenia, to date no study has compared metacognitive function between these groups. We aimed to compare the metacognitive capacities of persons with schizophrenia and ASD and their associations with other outcomes (neurocognition, social cognition, depression, and quality of life). Fifty-six outpatients with schizophrenia or ASD (mean age, 32.50 [9.05]; 67.9% male) were recruited from two French Centers of Reference for Psychiatric Rehabilitation of the REHABase cohort. Evaluation included the Indiana Psychiatric Illness Interview, Metacognition Assessment Scale-Abbreviated, Movie for the Assessment of Social Cognition, and a large cognitive battery. Compared with those with schizophrenia, participants with ASD had higher self-reflectivity (p = 0.025; odds ratio, 1.38 [1.05-1.86]) in univariable analyses. Metacognitive deficits may be found in ASD with a profile that varies from what is found in schizophrenia. It is possible that methods for enhancing metacognitive abilities during psychiatric rehabilitation may be refined to assist adults with ASD to better manage their own recovery.

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7. Ho A, Towheed A, Luong S, Zucker S, Fethke E. Clinical Discordance in Monozygotic Twins With Autism Spectrum Disorder. Cureus;2022 (May);14(5):e24813.

There is a significant concordance of autism spectrum disorder in monozygotic (MZ) twins, where behavioral manifestations are heavily influenced by genetic factors. We describe a case of male monozygotic twins with autism spectrum disorder (ASD), raised in the same household, that present with different clinical manifestations. One of the twins presents with intermittent frank syncopal episodes, sinus bradycardia, and elevated alkaline phosphatase (ALP), while the other has symptoms of attention-deficit/hyperactivity disorder (ADHD), normal cardiological findings, and normal ALP level. The clinical discordance in this pair of monozygotic twins may be due to any of the following: 1) neuroanatomic cerebellar differences, 2) variable expression of genotype, and 3) inconsistent neurotransmitter regulation.

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8. Jacob S, Anagnostou E, Hollander E, Jou R, McNamara N, Sikich L, Tobe R, Murphy D, McCracken J, Ashford E, Chatham C, Clinch S, Smith J, Sanders K, Murtagh L, Noeldeke J, Veenstra-VanderWeele J. Large multicenter randomized trials in autism: key insights gained from the balovaptan clinical development program. Mol Autism;2022 (Jun 11);13(1):25.

BACKGROUND: Autism spectrum disorder (ASD) is a common and heterogeneous neurodevelopmental condition that is characterized by the core symptoms of social communication difficulties and restricted and repetitive behaviors. At present, there is an unmet medical need for therapies to ameliorate these core symptoms in order to improve quality of life of autistic individuals. However, several challenges are currently faced by the ASD community relating to the development of pharmacotherapies, namely in the conduct of clinical trials. Balovaptan is a V1a receptor antagonist that has been investigated to improve social communication difficulties in individuals with ASD. In this viewpoint, we draw upon our recent first-hand experiences of the balovaptan clinical development program to describe current challenges of ASD trials. DISCUSSION POINTS: The balovaptan trials were conducted in a wide age range of individuals with ASD with the added complexities associated with international trials. When summarizing all three randomized trials of balovaptan, a placebo response was observed across several outcome measures. Placebo response was predicted by greater baseline symptom severity, online recruitment of participants, and less experienced or non-academic trial sites. We also highlight challenges relating to selection of outcome measures in ASD, the impact of baseline characteristics, and the role of expectation bias in influencing trial results. CONCLUSION: Taken together, the balovaptan clinical development program has advanced our understanding of the key challenges facing ASD treatment research. The insights gained can be used to inform and improve the design of future clinical trials with the collective aim of developing efficacious therapies to support individuals with ASD.

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9. Ji B, Jiang X, Luo Y. Autistic children’s age difference in affiliate stigma and resilience of their parents in China: A cross-sectional study. Arch Psychiatr Nurs;2022 (Aug);39:7-12.

BACKGROUND: Parents of children with Autism Spectrum Disorders (ASD) experience high levels of stigma, especially in China where the culture is shame socialized. Resilience can help overcome stigma; while parent characteristics predict resilience, other factors may also be significant such as the child’s age. OBJECTIVE: The study sought to identify the differences in affiliate stigma and resilience among Chinese parents of children with ASD according to the child’s age, and to determine whether the levels of resilience and experience of stigma are related. METHODS: A cross-sectional survey of 184 parents of children with ASD was conducted. Affiliate stigma and resilience were measured using the Chinese version of the 22-item Affiliate Stigma Scale and the Chinese version of the Connor-Davidson Resilience Scale. Differences were examined by using regression and correlation analysis. RESULTS: Parents of school-age children experienced more affiliate stigma than parents of preschoolers, but there was no difference in resilience when other factors were controlled. CONCLUSIONS: Considering the child’s age is important to understand affiliate stigma and resilience, particularly where resilience is protective and could inform the design of support strategies for preschooler parents.

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10. Kim H, Ahn JH, Lee JY, Jang YH, Kim YE, Kim JI, Kim BN, Lee HJ. Altered Cerebral Curvature in Preterm Infants Is Associated with the Common Genetic Variation Related to Autism Spectrum Disorder and Lipid Metabolism. J Clin Med;2022 (May 31);11(11)

Preterm births are often associated with neurodevelopmental impairment. In the critical developmental period of the fetal brain, preterm birth disrupts cortical maturation. Notably, preterm birth leads to alterations in the fronto-striatal and temporal lobes and the limbic region. Recent advances in MRI acquisition and analysis methods have revealed an integrated approach to the genetic influence on brain structure. Based on imaging studies, we hypothesized that the altered cortical structure observed after preterm birth is associated with common genetic variations. We found that the presence of the minor allele at rs1042778 in OXTR was associated with reduced curvature in the right medial orbitofrontal gyrus (p < 0.001). The presence of the minor allele at rs174576 in FADS2 (p < 0.001) or rs740603 in COMT (p < 0.001) was related to reduced curvature in the left posterior cingulate gyrus. This study provides biological insight into altered cortical curvature at term-equivalent age, suggesting that the common genetic variations related to autism spectrum disorder (ASD) and lipid metabolism may mediate vulnerability to early cortical dysmaturation in preterm infants.

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11. Lee A, Xu J, Wen Z, Jin P. Across Dimensions: Developing 2D and 3D Human iPSC-Based Models of Fragile X Syndrome. Cells;2022 (May 24);11(11)

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder. FXS is caused by a cytosine-guanine-guanine (CGG) trinucleotide repeat expansion in the untranslated region of the FMR1 gene leading to the functional loss of the gene’s protein product FMRP. Various animal models of FXS have provided substantial knowledge about the disorder. However, critical limitations exist in replicating the pathophysiological mechanisms. Human induced pluripotent stem cells (hiPSCs) provide a unique means of studying the features and processes of both normal and abnormal human neurodevelopment in large sample quantities in a controlled setting. Human iPSC-based models of FXS have offered a better understanding of FXS pathophysiology specific to humans. This review summarizes studies that have used hiPSC-based two-dimensional cellular models of FXS to reproduce the pathology, examine altered gene expression and translation, determine the functions and targets of FMRP, characterize the neurodevelopmental phenotypes and electrophysiological features, and, finally, to reactivate FMR1. We also provide an overview of the most recent studies using three-dimensional human brain organoids of FXS and end with a discussion of current limitations and future directions for FXS research using hiPSCs.

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12. Lim ET, Chan Y, Dawes P, Guo X, Erdin S, Tai DJC, Liu S, Reichert JM, Burns MJ, Chan YK, Chiang JJ, Meyer K, Zhang X, Walsh CA, Yankner BA, Raychaudhuri S, Hirschhorn JN, Gusella JF, Talkowski ME, Church GM. Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder. Nat Commun;2022 (Jun 10);13(1):3243.

Cerebral organoids can be used to gain insights into cell type specific processes perturbed by genetic variants associated with neuropsychiatric disorders. However, robust and scalable phenotyping of organoids remains challenging. Here, we perform RNA sequencing on 71 samples comprising 1,420 cerebral organoids from 25 donors, and describe a framework (Orgo-Seq) to integrate bulk RNA and single-cell RNA sequence data. We apply Orgo-Seq to 16p11.2 deletions and 15q11-13 duplications, two loci associated with autism spectrum disorder, to identify immature neurons and intermediate progenitor cells as critical cell types for 16p11.2 deletions. We further applied Orgo-Seq to identify cell type-specific driver genes. Our work presents a quantitative phenotyping framework to integrate multi-transcriptomic datasets for the identification of cell types and cell type-specific co-expressed driver genes associated with neuropsychiatric disorders.

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13. Mohamad Aun NS, Zakaria SM, Ahmad Badayai AR, Idris IB, Mohd Daud TI, Mohd Fazree SD. Quality of Life among Mothers of High Functioning Autism Spectrum Disorder (HFASD)Adolescents. Int J Environ Res Public Health;2022 (May 30);19(11)

Autism Spectrum Disorder (ASD) has become more prevalent globally. The disorder is predominantly characterised by low social skills noted explicitly in people with High Functioning Autism Spectrum Disorder (HFASD). The individuals usually possess a normal or superior intelligence quotient (IQ) but the disability impedes the achievement of their actual high potential, hence compromising their quality of life (QoL). Managing adversities encountered by children with HFASD often compromises the QoL of the entire family. Thus, this study aimed to identify specific domains of QoL among mothers of high-functioning autistic adolescents. The study assessed seven mothers of adolescents with HFASD using a semi-structured interview format. A thematic qualitative analysis was conducted to analyse the data. The results suggested that mothers perceived their QoL based on physical and emotional well-being, material well-being, interpersonal relationship, and environmental well-being. Intervention for HFASD is multidisciplinary, which targets a broad spectrum of symptoms and skills deficits and customises the programme to meet each individual’s different needs. Nonetheless, intervention facilities in Malaysia are seriously limited, particularly in supporting QoL for children with HFASD. Therefore, by identifying the domains of QoL would improve the mothers’ resilience in raising their children with HFASD.

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14. Movaghar A, Page D, Brilliant M, Mailick M. Advancing artificial intelligence-assisted pre-screening for fragile X syndrome. BMC Med Inform Decis Mak;2022 (Jun 10);22(1):152.

BACKGROUND: Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, is significantly underdiagnosed in the general population. Diagnosing FXS is challenging due to the heterogeneity of the condition, subtle physical characteristics at the time of birth and similarity of phenotypes to other conditions. The medical complexity of FXS underscores an urgent need to develop more efficient and effective screening methods to identify individuals with FXS. In this study, we evaluate the effectiveness of using artificial intelligence (AI) and electronic health records (EHRs) to accelerate FXS diagnosis. METHODS: The EHRs of 2.1 million patients served by the University of Wisconsin Health System (UW Health) were the main data source for this retrospective study. UW Health includes patients from south central Wisconsin, with approximately 33 years (1988-2021) of digitized health data. We identified all participants who received a code for FXS in the form of International Classification of Diseases (ICD), Ninth or Tenth Revision (ICD9 = 759.83, ICD10 = Q99.2). Only individuals who received the FXS code on at least two occasions (« Rule of 2 ») were classified as clinically diagnosed cases. To ensure the availability of sufficient data prior to clinical diagnosis to test the model, only individuals who were diagnosed after age 10 were included in the analysis. A supervised random forest classifier was used to create an AI-assisted pre-screening tool to identify cases with FXS, 5 years earlier than the time of clinical diagnosis based on their medical records. The area under receiver operating characteristic curve (AUROC) was reported. The AUROC shows the level of success in identification of cases and controls (AUROC = 1 represents perfect classification). RESULTS: 52 individuals were identified as target cases and matched with 5200 controls. AI-assisted pre-screening tool successfully identified cases with FXS, 5 years earlier than the time of clinical diagnosis with an AUROC of 0.717. A separate model trained and tested on UW Health cases achieved the AUROC of 0.798. CONCLUSIONS: This result shows the potential utility of our tool in accelerating FXS diagnosis in real clinical settings. Earlier diagnosis can lead to more timely intervention and access to services with the goal of improving patients’ health outcomes.

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15. Nandwana V, Nandwana NK, Das Y, Saito M, Panda T, Das S, Almaguel F, Hosmane NS, Das BC. The Role of Microbiome in Brain Development and Neurodegenerative Diseases. Molecules (Basel, Switzerland);2022 (May 25);27(11)

Hundreds of billions of commensal microorganisms live in and on our bodies, most of which colonize the gut shortly after birth and stay there for the rest of our lives. In animal models, bidirectional communications between the central nervous system and gut microbiota (Gut-Brain Axis) have been extensively studied, and it is clear that changes in microbiota composition play a vital role in the pathogenesis of various neurodevelopmental and neurodegenerative disorders, such as Autism Spectrum Disorder, Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, anxiety, stress, and so on. The makeup of the microbiome is impacted by a variety of factors, such as genetics, health status, method of delivery, environment, nutrition, and exercise, and the present understanding of the role of gut microbiota and its metabolites in the preservation of brain functioning and the development of the aforementioned neurological illnesses is summarized in this review article. Furthermore, we discuss current breakthroughs in the use of probiotics, prebiotics, and synbiotics to address neurological illnesses. Moreover, we also discussed the role of boron-based diet in memory, boron and microbiome relation, boron as anti-inflammatory agents, and boron in neurodegenerative diseases. In addition, in the coming years, boron reagents will play a significant role to improve dysbiosis and will open new areas for researchers.

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16. Ochi S, Manabe S, Kikkawa T, Osumi N. Thirty Years’ History since the Discovery of Pax6: From Central Nervous System Development to Neurodevelopmental Disorders. Int J Mol Sci;2022 (May 30);23(11)

Pax6 is a sequence-specific DNA binding transcription factor that positively and negatively regulates transcription and is expressed in multiple cell types in the developing and adult central nervous system (CNS). As indicated by the morphological and functional abnormalities in spontaneous Pax6 mutant rodents, Pax6 plays pivotal roles in various biological processes in the CNS. At the initial stage of CNS development, Pax6 is responsible for brain patterning along the anteroposterior and dorsoventral axes of the telencephalon. Regarding the anteroposterior axis, Pax6 is expressed inversely to Emx2 and Coup-TF1, and Pax6 mutant mice exhibit a rostral shift, resulting in an alteration of the size of certain cortical areas. Pax6 and its downstream genes play important roles in balancing the proliferation and differentiation of neural stem cells. The Pax6 gene was originally identified in mice and humans 30 years ago via genetic analyses of the eye phenotypes. The human PAX6 gene was discovered in patients who suffer from WAGR syndrome (i.e., Wilms tumor, aniridia, genital ridge defects, mental retardation). Mutations of the human PAX6 gene have also been reported to be associated with autism spectrum disorder (ASD) and intellectual disability. Rodents that lack the Pax6 gene exhibit diverse neural phenotypes, which might lead to a better understanding of human pathology and neurodevelopmental disorders. This review describes the expression and function of Pax6 during brain development, and their implications for neuropathology.

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17. Sauer AK, Hagmeyer S, Grabrucker AM. Prenatal Zinc Deficient Mice as a Model for Autism Spectrum Disorders. Int J Mol Sci;2022 (May 29);23(11)

Epidemiological studies have shown a clear association between early life zinc deficiency and Autism Spectrum Disorders (ASD). In line with this, mouse models have revealed prenatal zinc deficiency as a profound risk factor for neurobiological and behavioral abnormalities in the offspring reminiscent of ASD behavior. From these studies, a complex pathology emerges, with alterations in the gastrointestinal and immune system and synaptic signaling in the brain, as a major consequence of prenatal zinc deficiency. The features represent a critical link in a causal chain that leads to various neuronal dysfunctions and behavioral phenotypes observed in prenatal zinc deficient (PZD) mice and probably other mouse models for ASD. Given that the complete phenotype of PZD mice may be key to understanding how non-genetic factors can modify the clinical features and severity of autistic patients and explain the observed heterogeneity, here, we summarize published data on PZD mice. We critically review the emerging evidence that prenatal zinc deficiency is at the core of several environmental risk factors associated with ASD, being mechanistically linked to ASD-associated genetic factors. In addition, we highlight future directions and outstanding questions, including potential symptomatic, disease-modifying, and preventive treatment strategies.

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18. Schrott R, Greeson KW, King D, Symosko Crow KM, Easley CAt, Murphy SK. Cannabis alters DNA methylation at maternally imprinted and autism candidate genes in spermatogenic cells. Syst Biol Reprod Med;2022 (Jun 10):1-13.

Cannabis use in the United States is increasing, with highest consumption among men at their peak reproductive years. We previously demonstrated widespread changes in sperm DNA methylation with cannabis exposure in humans and rats, including genes important in neurodevelopment. Here, we use an in vitro human spermatogenesis model to recapitulate chronic cannabis use and assess DNA methylation at imprinted and autism spectrum disorder (ASD) candidate genes in spermatogonial stem cell (SSC)- and spermatid-like cells. Methylation at maternally imprinted genes SGCE and GRB10 was significantly altered in SSC- and spermatid-like cells, respectively, while PEG3 was significantly differentially methylated in spermatid-like cells. Two of ten randomly selected ASD candidate genes, HCN1 and NR4A2, had significantly altered methylation with cannabis exposure in SSC-like cells. These results support our findings in human cohorts and provide a new tool with which to gain mechanistic insights into the association between paternal cannabis use and risk of ASD in offspring.

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19. Seo SS, Louros SR, Anstey N, Gonzalez-Lozano MA, Harper CB, Verity NC, Dando O, Thomson SR, Darnell JC, Kind PC, Li KW, Osterweil EK. Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome. Nat Commun;2022 (Jun 10);13(1):3236.

Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu(1/5) activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu(1/5) -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1(-/y)). Our results identify a significant increase in the translation of ribosomal proteins (RPs) upon mGlu(1/5) stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1(-/y) neurons. Inhibiting RP translation significantly impairs mGluR-LTD and prevents the length-dependent shift in the translating population. Together, these results suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation.

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20. Sharma A, Bhalla S, Mehan S. PI3K/AKT/mTOR signalling inhibitor chrysophanol ameliorates neurobehavioural and neurochemical defects in propionic acid-induced experimental model of autism in adult rats. Metab Brain Dis;2022 (Jun 10)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder marked by social and communication deficits as well as repetitive behaviour. Several studies have found that overactivation of the PI3K/AKT/mTOR signalling pathways during brain development plays a significant role in autism pathogenesis. Overexpression of the PI3K/AKT/mTOR signalling pathway causes neurological disorders by increasing cell death, neuroinflammation, and oxidative stress. Chrysophanol, also known as chrysophanic acid, is a naturally occurring chemical obtained from the plant Rheum palmatum. This study aimed to examine the neuroprotective effect of CPH on neurobehavioral, molecular, neurochemical, and gross pathological alterations in ICV-PPA induced experimental model of autism in adult rats. The effects of ICV-PPA on PI3K/AKT/mTOR downregulation in the brain were studied in autism-like rats. Furthermore, we investigated how CPH affected myelin basic protein (MBP) levels in rat brain homogenate and apoptotic biomarkers such as caspase-3, Bax, and Bcl-2 levels in rat brain homogenate and blood plasma samples. Rats were tested for behavioural abnormalities such as neuromuscular dysfunction using an actophotometer, motor coordination using a beam crossing task (BCT), depressive behaviour using a forced swim test (FST), cognitive deficiency, and memory consolidation using a Morris water maze (MWM) task. In PPA-treated rats, prolonged oral CPH administration from day 12 to day 44 of the experimental schedule reduces autistic-like symptoms. Furthermore, in rat brain homogenates, blood plasma, and CSF samples, cellular, molecular, and cell death markers, neuroinflammatory cytokines, neurotransmitter levels, and oxidative stress indicators were investigated. The recent findings imply that CPH also restores abnormal neurochemical levels and may prevent autism-like gross pathological alterations, such as demyelination volume, in the rat brain.

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21. Sheng Z, Liu Q, Cheng C, Li M, Barash J, Kofke WA, Shen Y, Xie Z. Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b. Br J Anaesth;2022 (Jun 11)

BACKGROUND: Environmental factors contribute to autism spectrum disorder. Fentanyl, one of the most widely used opioid analgesics in anaesthesia, can induce neurotoxicity, but its role in autism remains unknown. We determined whether fentanyl induced autism-like behaviours in young mice and the underlying mechanisms. METHODS: Young male and female mice received fentanyl at postnatal days 6, 8, and 10, and performed behavioural tests, including three-chamber social preference, elevated plus maze, grooming behaviour, and open-field test, from postnatal days 30-32. Expression of Grin2b, the gene encoding the GluN2B subunit of the N-methyl-d-aspartate receptor, was assessed in the anterior cingulate cortex of male mice using fluorescence in situ hybridisation histochemistry. We used bisulfite target sequencing to determine Grin2b hypermethylation sites after fentanyl treatment. In the specific activation and rescue experiments, we injected the mu opioid receptor agonist [D-Ala,(2) N-MePhe,(4) Gly-ol]-enkephalin (DAMGO) or Grin2b overexpression lentivirus into the anterior cingulate cortex of male mice. RESULTS: Fentanyl induced autism-like behaviours in both young male and female mice, and downregulated Grin2b expression (0.49-fold [0.08] vs 1.00-fold [0.09]; P<0.01) and GluN2B protein amounts (0.38-fold [0.07] vs 1.00-fold [0.12]; P<0.01) in the anterior cingulate cortex through hypermethylation of Grin2b. The mu-opioid receptor antagonist naloxone and overexpression of Grin2b in anterior cingulate cortex attenuated the fentanyl-induced effects, whereas DAMGO injection into the anterior cingulate cortex induced autism-like behaviours. CONCLUSIONS: These data suggest that fentanyl induces autism-like behaviours in young mice via an epigenetic mechanism. Further research is required to determine possible clinical relevance to autism risk.

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22. Singla R, Mishra A, Lin H, Lorsung E, Le N, Tin S, Jin VX, Cao R. Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice. Int J Mol Sci;2022 (Jun 5);23(11)

Approximately 50-80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown. The essential clock gene Bmal1 (Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous Bmal1 deletion (Bmal1(+/-)) reduced the Bmal1 protein levels by ~50-75%. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Accordingly, Bmal1(+/-) mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD.

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23. Tovo PA, Davico C, Marcotulli D, Vitiello B, Daprà V, Calvi C, Montanari P, Carpino A, Galliano I, Bergallo M. Enhanced Expression of Human Endogenous Retroviruses, TRIM28 and SETDB1 in Autism Spectrum Disorder. Int J Mol Sci;2022 (May 25);23(11)

Human endogenous retroviruses (HERVs) are relics of ancestral infections and represent 8% of the human genome. They are no longer infectious, but their activation has been associated with several disorders, including neuropsychiatric conditions. Enhanced expression of HERV-K and HERV-H envelope genes has been found in the blood of autism spectrum disorder (ASD) patients, but no information is available on syncytin 1 (SYN1), SYN2, and multiple sclerosis-associated retrovirus (MSRV), which are thought to be implicated in brain development and immune responses. HERV activation is regulated by TRIM28 and SETDB1, which are part of the epigenetic mechanisms that organize the chromatin architecture in response to external stimuli and are involved in neural cell differentiation and brain inflammation. We assessed, through a PCR realtime Taqman amplification assay, the transcription levels of pol genes of HERV-H, -K, and -W families, of env genes of SYN1, SYN2, and MSRV, as well as of TRIM28 and SETDB1 in the blood of 33 ASD children (28 males, median 3.8 years, 25-75% interquartile range 3.0-6.0 y) and healthy controls (HC). Significantly higher expressions of TRIM28 and SETDB1, as well as of all the HERV genes tested, except for HERV-W-pol, were found in ASD, as compared with HC. Positive correlations were observed between the mRNA levels of TRIM28 or SETDB1 and every HERV gene in ASD patients, but not in HC. Overexpression of TRIM28/SETDB1 and several HERVs in children with ASD and the positive correlations between their transcriptional levels suggest that these may be main players in pathogenetic mechanisms leading to ASD.

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24. Urrutia-Ruiz C, Rombach D, Cursano S, Gerlach-Arbeiter S, Schoen M, Bockmann J, Demestre M, Boeckers TM. Deletion of the Autism-Associated Protein SHANK3 Abolishes Structural Synaptic Plasticity after Brain Trauma. Int J Mol Sci;2022 (May 29);23(11)

Autism spectrum disorders (ASDs) are characterized by repetitive behaviors and impairments of sociability and communication. About 1% of ASD cases are caused by mutations of SHANK3, a major scaffolding protein of the postsynaptic density. We studied the role of SHANK3 in plastic changes of excitatory synapses within the central nervous system by employing mild traumatic brain injury (mTBI) in WT and Shank3 knockout mice. In WT mice, mTBI triggered ipsi- and contralateral loss of hippocampal dendritic spines and excitatory synapses with a partial recovery over time. In contrast, no significant synaptic alterations were detected in Shank3∆11-/- mice, which showed fewer dendritic spines and excitatory synapses at baseline. In line, mTBI induced the upregulation of synaptic plasticity-related proteins Arc and p-cofilin only in WT mice. Interestingly, microglia proliferation was observed in WT mice after mTBI but not in Shank3∆11-/- mice. Finally, we detected TBI-induced increased fear memory at the behavioral level, whereas in Shank3∆11-/- animals, the already-enhanced fear memory levels increased only slightly after mTBI. Our data show the lack of structural synaptic plasticity in Shank3 knockout mice that might explain at least in part the rigidity of behaviors, problems in adjusting to new situations and cognitive deficits seen in ASDs.

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25. Vella Fondacaro D, Vella Fondacaro F, Camilleri N. A Qualitative Exploration of Parental Views When Comparing Individual to Group Sports in Children with Autism Spectrum Disorder-A Pilot Study. Int J Environ Res Public Health;2022 (Jun 5);19(11)

(1) Background: Physical activity is important for children with autism spectrum disorder. This study aimed to analyse autistic children’s and their parents’ preferences between group and individual physical activity, while exploring potential social barriers that they might encounter. (2) Methods: Retrospective analysis identified 701 new referrals received by the Maltese national child and adolescent mental health service, between 2016 and 2017. Of them, 24 received a sole diagnosis of autism and 10 were chosen via purposive sampling. A semi-structured interview guide was created, including readability testing, translation/back-translation, inter-rater agreements, and focus group testing. Parents were informed, consented, interviewed and thematic analysis carried out. Further quantitative data were tabled accordingly. (3) Results: Only one child met World Health Organisation recommendations for physical activity. More children preferred individual sports while parents described more benefits with group sports. Parents’ perceived benefits with group sports included better socialization, while improved levels of self-esteem and coping with anxiety were highlighted benefits for individual sports. Parents felt misunderstood, burnt out, and described a lack of autism-friendly sports facilities, including geographical disproportionation of adequate facilities on the island. Too much screen time was a major parental concern. (4) Conclusion: Recommendations aim to develop sport therapy systems and well-resourced services in Malta. Staff training is recommended to improve service quality.

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26. Yang YJ, Chung KM. Pilot Randomized Control Trial of an App-Based CBT Program for Reducing Anxiety in Individuals with ASD without Intellectual Disability. J Autism Dev Disord;2022 (Jun 10)

This study developed and tested the effectiveness of an app-based cognitive behavioral therapy (CBT) program in alleviating anxiety among adolescents and adults with autism without co-occurring intellectual disability. Thirty participants from 15 to 35 years old were randomly assigned to either the intervention or waitlist control group, and self- and caregiver proxy report questionnaires were administered, accompanied by direct behavior observation before and after the intervention period. There was a significant decrease in anxiety level, an increase in positive affect, and a decline in stereotypic behaviors, hyperactivity, noncompliance, and inappropriate speech in proxy reports for the intervention group, compared to the control group. A significant rise in passive response in the direct observation was also seen in the intervention group.

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27. Zhang B, Liang S, Chen J, Chen L, Chen W, Tu S, Hu L, Jin H, Chu L. Effectiveness of peer-mediated intervention on social skills for children with autism spectrum disorder: a randomized controlled trial. Transl Pediatr;2022 (May);11(5):663-675.

BACKGROUND: Peer-mediated intervention (PMI) is an intervention that teaches normally developing peers to help children with autism spectrum disorder (ASD) actively participate in social interactions. Previous studies have shown that PMI applied to school settings is effective for children with ASD, but more multiple-baseline single-subject design. Many questions are still not clear due to the large clinical variability in children with ASD. This study investigated the effectiveness of PMI on social skills of children with ASD at varying symptom levels and analyzed the specific changes. METHODS: This study used a randomized, single-blind, parallel-controlled design to analyze the effect of PMI in a hospital setting. Fifty-five children aged 4-12 years were diagnosed with ASD by clinicians using the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and stratified randomly allocated to either the experimental group or the control group using the envelope method. The experimental group utilized PMI, whereas the control group utilized behavioral therapy based on applied behavior analysis (ABA) [early intensive behavioral intervention (EIBI)]. This study primarily utilized the Social Responsiveness Scale (SRS) to evaluate the social performance of autistic children prior to and after the intervention. RESULTS: Fifty-five participants were recruited and analyzed, the experimental group (n=29; mild to moderate n=18, severe n=11) and the control group (n=26; mild to moderate n=15, severe n=11). After the intervention, the experimental group’s SRS score fell significantly more than the control group’s (t=-3.918, P=0.000), d=-1.043; the mild to moderate subgroup experienced the same situation (H=17.811, P=0.009), d=-1.642. At the same time, the decline in social communication scores was significantly greater in the experimental group compared to the control group (t=-3.869, P=0.000), and the 95% confidence interval was -10.067 to -3.193. The social motivation of the mild-to-moderate subgroup of the experimental group (H=16.894, P=0.011), -3.000 (25th percentile, 75th percentile: -3.000, 0.000), and the behavioral patterns of autism (H=18.150, P=0.006), -3.000 (25th percentile, 75th percentile: -5.000, 0.000), the decreased value was significantly larger. CONCLUSIONS: PMI therapy can increase social motivation in children with mild to moderate ASD, minimize undesirable behavior patterns, effectively improve overall social skills and enhance effective social communication with others. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100049185.

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28. Zhang W, Ross PJ, Ellis J, Salter MW. Targeting NMDA receptors in neuropsychiatric disorders by drug screening on human neurons derived from pluripotent stem cells. Transl Psychiatry;2022 (Jun 9);12(1):243.

NMDA receptors (NMDARs), a prominent subtype of glutamatergic receptors, are implicated in the pathogenesis and development of neuropsychiatric disorders such as epilepsy, intellectual disability, autism spectrum disorder, and schizophrenia, and are therefore a potential therapeutic target in treating these disorders. Neurons derived from induced pluripotent stem cells (iPSCs) have provided the opportunity to investigate human NMDARs in their native environment. In this review, we describe the expression, function, and regulation of NMDARs in human iPSC-derived neurons and discuss approaches for utilizing human neurons for identifying potential drugs that target NMDARs in the treatment of neuropsychiatric disorders. A challenge in studying NMDARs in human iPSC-derived neurons is a predominance of those receptors containing the GluN2B subunit and low synaptic expression, suggesting a relatively immature phenotype of these neurons and delayed development of functional NMDARs. We outline potential approaches for improving neuronal maturation of human iPSC-derived neurons and accelerating the functional expression of NMDARs. Acceleration of functional expression of NMDARs in human iPSC-derived neurons will improve the modeling of neuropsychiatric disorders and facilitate the discovery and development of novel therapeutics targeting NMDARs for the treatment of these disorders.

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