1. Berzhanskaya J, Phillips MA, Gorin A, Lai C, Shen J, Colonnese MT. {{Disrupted Cortical State Regulation in a Rat Model of Fragile X Syndrome}}. {Cereb Cortex}. 2016.
Children with Fragile X syndrome (FXS) have deficits of attention and arousal. To begin to identify the neural causes of these deficits, we examined juvenile rats lacking the Fragile X mental retardation protein (FMR-KO) for disruption of cortical activity related to attention and arousal. Specifically, we examined the switching of visual cortex between activated and inactivated states that normally occurs during movement and quiet rest, respectively. In both wild-type and FMR-KO rats, during the third and fourth postnatal weeks cortical activity during periods of movement was dominated by an activated state with prominent 18-52 Hz activity. However, during quiet rest, when activity in wild-type rats became dominated by the inactivated state (3-9 Hz activity), FMR-KO rat cortex abnormally remained activated, resulting in increased high-frequency and reduced low-frequency power during rest. Firing rate correlations revealed reduced synchronization in FMR-KO rats, particularly between fast-spiking interneurons, that developmentally precede cortical state defects. Together our data suggest that disrupted inhibitory connectivity impairs the ability of visual cortex to regulate exit from the activated state in a behaviorally appropriate manner, potentially contributing to disrupted attention and sensory processing observed in children with FXS by making it more difficult to decrease cortical drive by unattended stimuli.
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2. Businaro R, Corsi M, Azzara G, Di Raimo T, Laviola G, Romano E, Ricci L, Maccarrone M, Aronica E, Fuso A, Ricci S. {{Interleukin-18 modulation in autism spectrum disorders}}. {J Neuroinflammation}. 2016; 13(1): 2.
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease which affects 1 in 88 children. Its etiology remains basically unknown, but it is apparent that neuroinflammation is involved in disease development. Great attention has been focused on pro-inflammatory cytokines, and several studies have reported their dysfunction unbalance in serum as well as in the brain. The present work aimed at evaluating putative dysregulation of interleukin-18 (IL-18), a pro-inflammatory cytokine of the IL-1 family in the sera of patients with ASD of different grades, compared to healthy controls, as well as in postmortem brain samples obtained from patients with tuberous sclerosis as well as acute inflammatory diseases. Moreover, quantitative analysis of IL-18 was performed in the sera and brain obtained from Reeler mice, an experimental model of autism. METHODS: Serum IL-18 levels were measured by ELISA. IL-18 was localized by immunohistochemical analysis in brain sections obtained from tuberous sclerosis and encephalitis patients, as well as from gender- and age-matched controls, and in the brain sections of both Reeler and wild-type mice. IL-18 was also quantified by Western blots in homogenates of Reeler and wild-type mice brains. IL-18 binding protein (IL-18BP) was evaluated in Reeler and wild-type mice plasma as well as in their brains (sections and homogenates). RESULTS: IL-18 content decreased in the sera of patients with autism compared to healthy subjects and in Reeler sera compared to wild-type controls. IL-18 was detected within glial cells and neurons in the brain of subjects affected by tuberous sclerosis and encephalitis whereas in healthy subjects, only a weak IL-18 positivity was detected at the level of glial cells. Western blot identified higher amounts of IL-18 in Reeler brain homogenates compared to wild-type littermates. IL-18BP was expressed in higher amounts in Reeler brain compared to the brain of wild-type mice, whereas no significant difference was detected comparing IL-18BP plasma levels. CONCLUSIONS: IL-18 is dysregulated in ASD patients. Further studies seemed necessary to clarify the molecular details behind IL-18 increase in the brain and IL-18 decrease in the sera of patients. An increase in the size of the patient cohort seems necessary to ascertain whether decreased IL-18 content in the sera can become a predictive biomarker of ASD and whether its measure, in combination with other markers (e.g., increased levels of brain-derived neurotrophic factor (BDNF)), may be included in a diagnostic panel.
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3. Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, Robinson EB, Churchill SE, Kohane IS, Perlis RH. {{Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study}}. {Transl Psychiatry}. 2016; 6: e708.
Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results. Precisely estimating such risk, if any, is of great importance in light of the need to balance such risk with the benefit of depression and anxiety treatment. We developed a method to integrate data from multiple New England health systems, matching offspring and maternal health data in electronic health records to characterize diagnoses and medication exposure. Children with ASD or ADHD were matched 1:3 with children without neurodevelopmental disorders. Association between maternal antidepressant exposure and ASD or ADHD liability was examined using logistic regression, adjusting for potential sociodemographic and psychiatric confounding variables. In new cohorts of 1245 ASD cases and 1701 ADHD cases, along with age-, sex- and socioeconomic status matched controls, neither disorder was significantly associated with prenatal antidepressant exposure in crude or adjusted models (adjusted odds ratio 0.90, 95% confidence interval 0.50-1.54 for ASD; 0.97, 95% confidence interval 0.53-1.69 for ADHD). Pre-pregnancy antidepressant exposure significantly increased risk for both disorders. These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication. They further demonstrate the potential to integrate data across electronic health records studies spanning multiple health systems to enable efficient pharmacovigilance investigation.
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4. de la Marche W, Noens I, Steyaert J. {{[Dimensional measures in autism spectrum disorders: do we know what we measure?]}}. {Tijdschr Psychiatr}. 2015; 57(12): 897-901.
BACKGROUND: In the last decades, researchers often used measures to quantify autism spectrum disorder (ASD) traits, paralleling the tendency to describe psychiatric and developmental disorders more dimensionally. The broader autism phenotype (BAP) concept originates from this kind of research. AIM: The primary aim of our studies was to study the existence of the BAP and the familial transmission of quantitative autism traits (QAT). METHOD: We measured ASD-traits with interviews and questionnaires in all members of 170 families with at least one child with ASD. RESULTS: We confirmed the existence of the BAP in fathers, as well as the familial transmission of QAT. The results also suggest that what is measured with these questionnaires might depend on the population and the context. CONCLUSION: Based on our results and additional data from scientific literature, we reflect on the interpretations of research results and the use of quantitative scales in both research and clinical practice.
5. Diaz-Beltran L, Esteban FJ, Wall DP. {{A common molecular signature in ASD gene expression: following Root 66 to autism}}. {Transl Psychiatry}. 2016; 6: e705.
Several gene expression experiments on autism spectrum disorders have been conducted using both blood and brain tissue. Individually, these studies have advanced our understanding of the molecular systems involved in the molecular pathology of autism and have formed the bases of ongoing work to build autism biomarkers. In this study, we conducted an integrated systems biology analysis of 9 independent gene expression experiments covering 657 autism, 9 mental retardation and developmental delay and 566 control samples to determine if a common signature exists and to test whether regulatory patterns in the brain relevant to autism can also be detected in blood. We constructed a matrix of differentially expressed genes from these experiments and used a Jaccard coefficient to create a gene-based phylogeny, validated by bootstrap. As expected, experiments and tissue types clustered together with high statistical confidence. However, we discovered a statistically significant subgrouping of 3 blood and 2 brain data sets from 3 different experiments rooted by a highly correlated regulatory pattern of 66 genes. This Root 66 appeared to be non-random and of potential etiologic relevance to autism, given their enriched roles in neurological processes key for normal brain growth and function, learning and memory, neurodegeneration, social behavior and cognition. Our results suggest that there is a detectable autism signature in the blood that may be a molecular echo of autism-related dysregulation in the brain.
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6. Foster NE, Ouimet T, Tryfon A, Doyle-Thomas K, Anagnostou E, Hyde KL. {{Effects of Age and Attention on Auditory Global-Local Processing in Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2016.
In vision, typically-developing (TD) individuals perceive « global » (whole) before « local » (detailed) features, whereas individuals with autism spectrum disorder (ASD) exhibit a local bias. However, auditory global-local distinctions are less clear in ASD, particularly in terms of age and attention effects. To these aims, here ASD and TD children judged local and global pitch structure in nine-tone melodies. Both groups showed a similar global precedence effect, but ASD children were less sensitive to global interference than TD children at younger ages. There was no effect of attention task. These findings provide novel evidence of developmental differences in auditory perception and may help to refine sensory phenotypes in ASD.
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7. Kumar A, Juneja M, Mishra D. {{Prevalence of Autism Spectrum Disorders in Siblings of Indian Children With Autism Spectrum Disorders}}. {J Child Neurol}. 2016.
This study determined the prevalence of autism spectrum disorders in 201 siblings of children with autism spectrum disorders. Siblings were screened using Modified Checklist for Autism in Toddlers and Social Responsiveness Scale, parent version. Screen-positive siblings were assessed using Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria. The risk of autism spectrum disorder in siblings was correlated with various familial and disease characteristics of the index case. Prevalence of autism spectrum disorder in siblings was 4.97%. There was a significant effect of the presence of aggressive behavior, externalizing problems and total problems in the proband, assessed using Childhood Behavior Checklist, and the young age of the father at conception on sibling risk of autism spectrum disorder. Results of our study are in line with previous studies reporting similar prevalence but have also brought up the association with behavioral problems as a possible risk factor. Siblings of children with autism spectrum disorder should be routinely screened, and genetic counseling for this increased risk should be explained to the family.
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8. Matelski L, Van de Water J. {{Risk factors in autism: Thinking outside the brain}}. {J Autoimmun}. 2015.
Autism spectrum disorders (ASD) are complex neurodevelopmental conditions that have been rising markedly in prevalence for the past 30 years, now thought to affect 1 in 68 in the United States. This has prompted the search for possible explanations, and has even resulted in some controversy regarding the « true » prevalence of autism. ASD are influenced by a variety of genetic, environmental, and possibly immunological factors that act during critical periods to alter key developmental processes. This can affect multiple systems and manifests as the social and behavioral deficits that define these disorders. The interaction of environmental exposures in the context of an individual’s genetic susceptibilities manifests differently in each case, leading to heterogeneous phenotypes and varied comorbid symptoms within the disorder. This has also made it very difficult to elucidate underlying genes and exposure profiles, but progress is being made in this area. Some pharmaceutical drugs, toxicants, and metabolic and nutritional factors have been identified in epidemiological studies as increasing autism risk, especially during the prenatal period. Immunologic risk factors, including maternal infection during pregnancy, autoantibodies to fetal brain proteins, and familial autoimmune disease, have consistently been observed across multiple studies, as have immune abnormalities in individuals with ASD. Mechanistic research using animal models and patient-derived stem cells will help researchers to understand the complex etiology of these neurodevelopmental disorders, which will lead to more effective therapies and preventative strategies. Proposed therapies that need more investigation include special diets, probiotics, immune modulation, oxytocin, and personalized pharmacogenomic targets. The ongoing search for biomarkers and better treatments will result in earlier identification of ASD and provide much needed help and relief for afflicted families.
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9. Peng Y, Lu Z, Li G, Piechowicz M, Anderson M, Uddin Y, Wu J, Qiu S. {{The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain}}. {Mol Psychiatry}. 2016.
The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which has a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD.Molecular Psychiatry advance online publication, 5 January 2016; doi:10.1038/mp.2015.182.
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10. Russell S, McCloskey CR. {{Parent Perceptions of Care Received by Children With an Autism Spectrum Disorder}}. {J Pediatr Nurs}. 2015.
Research in the post-genomic era has provided substantial contributions toward identification of medical, genetic and environmental heritability factors associated with autism spectrum disorder (ASD). A specific etiology related to the diagnosis remains unclear, although prevalence statistics continue to rise with profound impact on families and their primary care providers (PCPs). Support professionals encounter significant challenges delivering comprehensive management for this complex neurobehavioral and developmental disorder. Children with ASD experience significantly higher risk for unmet healthcare needs, and parents report less satisfaction with their care although current literature does not fully explain why this issue persists. This study sought parent insight for the missing answers needed to inform practice. Eleven parents of children with an ASD participated in the study. Parent perceptions of care were examined utilizing Interpretive Phenomenological Analysis (IPA) and the Measure of Process of Care (MPOC-20) to illuminate and describe their lived experiences raising children with ASD, and interactions with their PCPs. Most parents utilized their child’s PCP for general health maintenance, and many felt their PCP was unable to manage issues specifically related to their child’s ASD. Most did not have an expectation for support with behavioral management in the home and school setting or identification of community and mental health resources, although many struggled with unaddressed needs in both of these realms. Utilizing parent perceptions to highlight practice deficiencies can build a foundation for care models that are more comprehensive and family centered.
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11. Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z, Carromeu C, Muotri AR, Marchetto MC, Gage FH, Chen G. {{KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome}}. {Proc Natl Acad Sci U S A}. 2016.
Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K+-Cl- cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.
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12. Zatkova M, Bakos J, Hodosy J, Ostatnikova D. {{Synapse alterations in autism: Review of animal model findings}}. {Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub}. 2016.
BACKGROUND: Recent research has produced an explosion of experimental data on the complex neurobiological mechanisms of developmental disorders including autism. Animal models are one approach to studying the phenotypic features and molecular basis of autism. In this review, we describe progress in understanding synaptogenesis and alterations to this process with special emphasis on the cell adhesion molecules and scaffolding proteins implicated in autism. Genetic mouse model experiments are discussed in relation to alterations to selected synaptic proteins and consequent behavioral deficits measured in animal experiments. METHODS: Pubmed databases were used to search for original and review articles on animal and human clinical studies on autism. RESULTS: The cell adhesion molecules, neurexin, neurolignin and the Shank family of proteins are important molecular targets associated with autism. CONCLUSION: The heterogeneity of the autism spectrum of disorders limits interpretation of information acquired from any single animal model or animal test. We showed synapse-specific/ model-specific defects associated with a given genotype in these models. Characterization of mouse models with genetic variations may help study the mechanisms of autism in humans. However, it will be necessary to apply new analytic paradigms in using genetically modified mice for understanding autism etiology in humans. Further studies are needed to create animal models with mutations that match the molecular and neural bases of autism.
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13. Zheng F, Kasper LH, Bedford DC, Lerach S, Teubner BJ, Brindle PK. {{Mutation of the CH1 Domain in the Histone Acetyltransferase CREBBP Results in Autism-Relevant Behaviors in Mice}}. {PLoS One}. 2016; 11(1): e0146366.
Autism spectrum disorders (ASDs) are a group of neurodevelopmental afflictions characterized by repetitive behaviors, deficits in social interaction, and impaired communication skills. For most ASD patients, the underlying causes are unknown. Genetic mutations have been identified in about 25 percent of ASD cases, including mutations in epigenetic regulators, suggesting that dysregulated chromatin or DNA function is a critical component of ASD. Mutations in the histone acetyltransferase CREB binding protein (CBP, CREBBP) cause Rubinstein-Taybi Syndrome (RTS), a developmental disorder that includes ASD-like symptoms. Recently, genomic studies involving large numbers of ASD patient families have theoretically modeled CBP and its paralog p300 (EP300) as critical hubs in ASD-associated protein and gene interaction networks, and have identified de novo missense mutations in highly conserved residues of the CBP acetyltransferase and CH1 domains. Here we provide animal model evidence that supports this notion that CBP and its CH1 domain are relevant to autism. We show that mice with a deletion mutation in the CBP CH1 (TAZ1) domain (CBPDeltaCH1/DeltaCH1) have an RTS-like phenotype that includes ASD-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity. Our results therefore indicate that loss of CBP CH1 domain function contributes to RTS, and possibly ASD, and that this domain plays an essential role in normal motor function, cognition and social behavior. Although the key physiological functions affected by ASD-associated mutation of epigenetic regulators have been enigmatic, our findings are consistent with theoretical models involving CBP and p300 in ASD, and with a causative role for recently described ASD-associated CBP mutations.
