GABA/Glutamate Neuron Differentiation Imbalance and Increased AKT/mTOR Signaling in CNTNAP2−/− Cerebral Organoids

Impact of acamprosate on plasma amyloid-β precursor protein in youth: A pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker

Autism spectrum disorders (ASDs) are a set of disorders characterised by social and communication deficits caused by numerous genetic lesions affecting brain development. Progress in ASD research has been hampered by the lack of appropriate models, as both 2D cell culture as well as animal models cannot fully recapitulate the developing human brain or the pathogenesis of ASD. Recently, cerebral organoids have been developed to provide a more accurate, 3D in vitro model of human brain development. Cerebral organoids have been shown to recapitulate the foetal brain gene expression profile, transcriptome, epigenome, as well as disease dynamics of both idiopathic and syndromic ASDs. They are thus an excellent tool to investigate development of foetal stage ASDs, as well as interventions that can reverse or rescue the altered phenotypes observed. In this review, we discuss the development of cerebral organoids, their recent applications in the study of both syndromic and idiopathic ASDs, their use as an ASD drug development platform, as well as limitations of their use in ASD research.

From the Early Emergence of Psychiatry to Stem Cells and Neural Organoids.

Purpose Question-asking serves as a tool to learn new information and is important in both academic and social settings. Boys with idiopathic autism spectrum disorder (ASD) and boys with fragile X syndrome and comorbid ASD (FXS + ASD) have similar social communication deficits, which may have downstream effects on their question-asking ability. This study examined question-asking in school-age boys with idiopathic ASD and FXS + ASD, including the role of ASD severity, expressive grammatical complexity (measured by mean length of utterance [MLU]), and IQ. Method Twenty-five boys with FXS + ASD and 21 boys with idiopathic ASD (ages 9-16 years) were included in this study. Autism Diagnostic Observation Schedule assessments were transcribed and coded for the frequency, function, and appropriateness of spontaneous questions asked. We examined group differences in these aspects of question-asking and relationships between question-asking and ASD severity, MLU, and IQ within each group. Results Boys with FXS + ASD asked more questions than boys with idiopathic ASD, although boys with idiopathic ASD asked a higher proportion of appropriate questions. Boys with idiopathic ASD also asked the examiner more personal questions than the boys with FXS + ASD. ASD severity and MLU were related to the proportion of clarification questions in FXS + ASD, and ASD severity was also related to the proportion of personal questions in this group. For the boys with idiopathic ASD, ASD severity was related to the total number of questions asked. Conclusions Our findings highlight similarities and differences between boys with FXS + ASD and idiopathic ASD in their spontaneous question production and indicate that ASD severity and grammatical language are differentially important for question-asking. This study has implications for targeted treatment in question-asking skills for boys with FXS + ASD and ASD.

Understanding the unique expressive language profiles of children with phenotypically similar, but distinct neurodevelopmental disorders, such as idiopathic autism spectrum disorder and fragile X syndrome with a co-diagnosis of autism spectrum disorder (fragile X syndrome + autism spectrum disorder), has both clinical and theoretical implications. However, comparative studies of these two clinical groups have been limited, and results have been inconsistent, partially as a result of different assessment methods being utilized. Thus, the current study compared the expressive language profiles of boys with idiopathic autism spectrum disorder and boys with fragile X syndrome + autism spectrum disorder and examined whether a similar linguistic profile emerged across different language sampling contexts: a semi-structured conversation and the Autism Diagnostic Observation Schedule. Eighteen boys with autism spectrum disorder (Mage = 13.25 years) and 19 boys with fragile X syndrome + autism spectrum disorder (Mage = 12.19 years), matched on autism spectrum disorder symptom severity and similar in terms of chronological age and mean length of utterance, participated in this study. Boys produced two language samples: one semi-structured conversation and one taken from the Autism Diagnostic Observation Schedule. Language samples were coded for talkativeness, lexical diversity, mean length of utterance, intelligibility, and repetitive or perseverative language. Analyses revealed that boys with autism spectrum disorder produced language samples that were more lexically diverse and intelligible, and that included less topic perseveration compared to boys with fragile X syndrome + autism spectrum disorder. With regards to sampling context, boys in both groups were more talkative and produced longer and more intelligible utterances in their conversation sample compared to their Autism Diagnostic Observation Schedule sample. However, boys with autism spectrum disorder and fragile X syndrome + autism spectrum disorder used a higher proportion of topic perseveration during the conversation sample. Overall, we found similarities as well as distinctions in the expressive language profiles of boys with fragile X syndrome + autism spectrum disorder and boys with idiopathic autism spectrum disorder. Moreover, the Autism Diagnostic Observation Schedule sample elicited a relatively different language profile than the conversation sample for boys in both groups. These findings help to further elucidate the unique language phenotypes of boys with idiopathic autism spectrum disorder and boys with fragile X syndrome + autism spectrum disorder. Moreover, our findings indicate that multiple language samples may be needed to obtain a comprehensive account of a child's expressive language ability.

BackgroundPotocki-Lupski syndrome (PTLS) and Smith-Magenis syndrome (SMS) are related genomic disorders, as duplication 17p11.2 (associated with PTLS) is the reciprocal recombination product of the SMS microdeletion. While SMS has a relatively well-delineated behavioural phenotype, the behavioural profile in PTLS is less well defined, despite purported associations with autism spectrum disorder (ASD) and the suggestion that some behaviours may be diametric to those seen in SMS.MethodsCaregivers of individuals with PTLS (N = 34; M age = 12.43, SD = 6.78) completed online behavioural questionnaires, including the Challenging Behaviour Questionnaire (CBQ), the Activity Questionnaire (TAQ), the Repetitive Behaviour Questionnaire (RBQ), the Mood, Interest and Pleasure Questionnaire-Short Form (MIPQ-S) and the Social Communication Questionnaire (SCQ), which assesses behaviours associated with ASD. Individuals with PTLS were matched on age and adaptive functioning to individuals with SMS (N = 31; M age = 13.61, SD = 6.85) and individuals with idiopathic ASD (N = 33; M age = 12.04, SD = 5.85) from an existing dataset.ResultsIndividuals with PTLS and SMS were less impaired than those with idiopathic ASD on the communication and reciprocal social interaction subscales of the SCQ, but neither syndrome group differed from idiopathic ASD on the restricted, repetitive and stereotyped behaviours subscale. On the repetitive behaviour measure, individuals with PTLS and idiopathic ASD scored higher than individuals with SMS on the compulsive behaviour subscale. Rates of self-injury and property destruction were significantly lower in PTLS and idiopathic ASD than in SMS. No between-syndrome differences were found in relation to overactivity or mood; however, impulsivity was greater in SMS than in PTLS.ConclusionsFindings suggest some overlap in the behavioural phenotype of PTLS and features of ASD symptomatology; however, the overall profile of behaviours in PTLS appears to be divergent from both idiopathic ASD and SMS. Relative to idiopathic ASD, PTLS is not characterised by communication or social interaction deficits. However, restricted and repetitive behaviours were evident in PTLS, and these may be characterised specifically by compulsive behaviours. While several behavioural differences were identified between PTLS and SMS, there was little evidence of diametric behavioural phenotypes, particularly in relation to social behaviour.

Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders that affect communication and social interactions and present with restricted interests and repetitive behavior patterns. The susceptibility to ASD is strongly influenced by genetic/heritable factors; however, there is still a large gap in understanding the cellular and molecular mechanisms underlying the neurobiology of ASD. Significant progress has been made in identifying ASD risk genes and the possible convergent pathways regulated by these gene networks during development. The breakthrough of cellular reprogramming technology has allowed the generation of induced pluripotent stem cells (iPSCs) from individuals with syndromic and idiopathic ASD, providing patient-specific cell models for mechanistic studies. In the past decade, protocols for developing brain organoids from these cells have been established, leading to significant advances in the in vitro reproducibility of the early steps of human brain development. Here, we reviewed the most relevant literature regarding the application of brain organoids to the study of ASD, providing the current state of the art, and discussing the impact of such models on the field, limitations, and opportunities for future development.

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.

Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined, neurodevelopmental disorder that has been modeled as a brain-based disease. The behavioral and cognitive features of ASD are associated with pervasive atypicalities in the central nervous system (CNS). To date, the exact mechanisms underlying the pathophysiology of ASD still remain unknown and there is currently no cure or effective treatment for this disorder. Many publications implicated the association of ASD with inflammation, immune dysregulation, neurotransmission dysfunction, mitochondrial impairment and cell signaling dysregulation. This review attempts to highlight evidence of the major pathophysiology of ASD including abnormalities in the brain structure and function, neuroglial activation and neuroinflammation, glutamatergic neurotransmission, mitochondrial dysfunction and mechanistic target of rapamycin (mTOR) signaling pathway dysregulation. Molecular and cellular factors that contributed to the pathogenesis of ASD and how they may affect the development and function of CNS are compiled in this review. However, findings of published studies have been complicated by the fact that autism is a very heterogeneous disorder; hence, we addressed the limitations that led to discrepancies in the reported findings. This review emphasizes the need for future studies to control study variables such as sample size, gender, age range and intelligence quotient (IQ), all of which that could affect the study measurements. Neuroinflammation or immune dysregulation, microglial activation, genetically linked neurotransmission, mitochondrial dysfunctions and mTOR signaling pathway could be the primary targets for treating and preventing ASD. Further research is required to better understand the molecular causes and how they may contribute to the pathophysiology of ASD.

Pragmatic language, or the use of language in social contexts, is a critical skill in daily life, supporting social interactions and the development of meaningful social relationships. Pragmatic language is universally impacted in autism spectrum disorder (ASD) and pragmatic deficits are also common in other neurodevelopmental conditions, particularly those related to ASD, such as fragile X syndrome (FXS). This study used a multi-method, longitudinal approach to characterize potentially unique pragmatic profiles across different neurodevelopmental disabilities, and across contexts that varied in degree of social demand. The utility of computational linguistic analyses, as an efficient tool for capturing pragmatic abilities, was also explored. Pragmatic skills of boys with idiopathic ASD (ASD-O, n = 43), FXS with and without ASD (FXS-ASD, n = 57; FXS-O, n = 14), Down syndrome (DS, n = 22), and typical development (TD, n = 24) were compared using variables obtained from a standardized measure, narrative, and semi-naturalistic conversation at up to three time points. Pragmatic language was most significantly impacted among males with ASD-O and FXS-ASD across all three contexts, with more difficulties in the least structured context (conversation), and also some differences based on FXS comorbidity. Patterns of group differences were more nuanced for boys with FXS-O and DS, with context having less of an impact. Clinical groups demonstrated minimal changes in pragmatic skills with age, with some exceptions. Computational language measurement tools showed some utility for measuring pragmatic skills, but were not as successful as traditional methods at capturing differences between clinical groups. Overlap and differences between ASD and other forms of neurodevelopmental disability in general, and between idiopathic and syndromic ASD in particular, have important implications for developing precisely tailored assessment and intervention approaches, consistent with a personalized medicine approach to clinical study and care in ASD.

“A developmental disability that hinders the normal functioning of the brain, affecting, in varying degrees, communication skills and social interaction. Repetitive behaviours, and different ways of learning, paying attention, or reacting to things are often distinctive signs”. This standard definition of autism fails to describe the complexity of a condition that ranges in its manifestations from severe intellectual impairment to superior cognitive skills, like in the Asperger syndrome. To comprise such diversity, autism disorders are now covered under the umbrella term “autism spectrum disorder” (ASD). In most cases, ASD manifests during the first 5 years of life, with boys significantly more likely to be diagnosed than girls. ASD usually goes together with several other problems that frequently include anxiety, sleep disorders, or epilepsy. No cure exists; treatment, such as speech therapy, just attempts to alleviate specific deficits of autistic patients. > Nothing is simple in autism. Even the real number of people affected is uncertain. Nothing is simple in autism. Even the real number of people affected is uncertain. The US CDC estimates that about 1 in 68 (or 1.5%) of children in the USA are living with ASD (http://www.cdc.gov/ncbddd/autism/data.html). The WHO has a more conservative estimate, last revised in January this year, of 1 in 160 children, based on a larger set of epidemiological surveys (http://www.who.int/mediacentre/factsheets/autism-spectrum-disorders/en/). Needless to say, most studies were conducted in developed countries, and the prevalence of ASD in many low‐ and middle‐income countries remains largely unknown. > Along the years, many potential causes have been indicated, including genetic and environmental factors, exposure to toxins during pregnancy, wide gaps between parent ages, and so on Although the general consensus is that prevalence rates are increasing globally, this point is debated too. Some analyses indicate that a large percentage of the increase in ASD owes to improved awareness and …

IntroductionChildren with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children...

BackgroundCHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8+/−) vs isogenic controls (CHD8+/−), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8+/− neuronal cells.MethodsIn the current study, RNA-seq was carried out on CHD8+/− and isogenic control (CHD8+/+) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon.ResultsTCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/β-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8+/− DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/β-catenin signaling in a subgroup of affected individuals.ConclusionsOverall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets—an important consideration for developing novel therapeutics in genetically heterogeneous complex traits.

Autism Spectrum Disorder (ASD) is a behavioral syndrome caused by complex genetic and non-genetic risk factors. It has been proposed that these risk factors lead to alterations in the development and 'wiring' of brain circuits and hence, the emergence of ASD. Although several lines of research lend support to this theory, etiological and clinical heterogeneity, methodological issues and inconsistent findings have led to significant doubts. One of the best established, albeit rare, causes of ASD is the genetic condition Tuberous Sclerosis Complex (TSC), where 40% of individuals develop ASD. A recent study by Peters and Taquet et al. analyzed electroencephalography (EEG) data using graph theory to model neural 'connectivity' in individuals with TSC with and without ASD and cases with 'idiopathic' ASD. TSC cases exhibited global under-connectivity and abnormal network topology, whereas individuals with TSC + ASD demonstrated similar connectivity patterns to those seen in individuals with idiopathic ASD: decreased long- over short-range connectivity. The similarity in connectivity abnormalities in TSC + ASD and ASD suggest a common final pathway and provide further support for 'mis-wired' neural circuitry in ASD. The origins of the connectivity changes, and their role in mediating between the neural and the cognitive/behavioral manifestations, will require further study.Please see related research article here http://www.biomedcentral.com/1741-7015/11/54