SHANK proteins: roles at the synapse and in autism spectrum disorder.

Several large-scale genomic studies have supported an association between cases of autism spectrum disorder and mutations in the genes SH3 and multiple ankyrin repeat domains protein 1 (SHANK1), SHANK2 and SHANK3, which encode a family of postsynaptic scaffolding proteins that are present at glutamatergic synapses in the CNS. An evaluation of human genetic data, as well as of in vitro and in vivo animal model data, may allow us to understand how disruption of SHANK scaffolding proteins affects the structure and function of neural circuits and alters behaviour.

Neuroinflammation in Autism: Plausible Role of Maternal Inflammation, Dietary Omega 3, and Microbiota.

Several genetic causes of autism spectrum disorder (ASD) have been identified. However, more recent work has highlighted that certain environmental exposures early in life may also account for some cases of autism. Environmental insults during pregnancy, such as infection or malnutrition, seem to dramatically impact brain development. Maternal viral or bacterial infections have been characterized as disruptors of brain shaping, even if their underlying mechanisms are not yet fully understood. Poor nutritional diversity, as well as nutrient deficiency, is strongly associated with neurodevelopmental disorders in children. For instance, imbalanced levels of essential fatty acids, and especially polyunsaturated fatty acids (PUFAs), are observed in patients with ASD and other neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder (ADHD) and schizophrenia). Interestingly, PUFAs, and specifically n-3 PUFAs, are powerful immunomodulators that exert anti-inflammatory properties. These prenatal dietary and immunologic factors not only impact the fetal brain, but also affect the microbiota. Recent work suggests that the microbiota could be the missing link between environmental insults in prenatal life and future neurodevelopmental disorders. As both nutrition and inflammation can massively affect the microbiota, we discuss here how understanding the crosstalk between these three actors could provide a promising framework to better elucidate ASD etiology.

Association of Peripheral Blood Levels of Brain-Derived Neurotrophic Factor With Autism Spectrum Disorder in Children: A Systematic Review and Meta-analysis.

Importance: Accumulating evidence suggests that brain-derived neurotrophic factor (BDNF) may be implicated in the developmental outcomes of children with autism spectrum disorder (ASD). Objective: To use meta-analysis to determine whether children with ASD have altered peripheral blood levels of BDNF. Data Source: A systematic search of PubMed, PsycINFO, and Web of Science was performed for English-language literature through February 7, 2016. The search terms included brain-derived neurotrophic factor or BDNF in combination with autism, without year restriction. Two additional records were retrieved after a review of the reference lists of selected articles. Study Selection: Studies were included if they provided data on peripheral blood levels of BDNF in children with ASD and healthy control children. Studies that included adults or with overlapping samples were excluded. Data Extraction and Synthesis: Data were extracted by 2 independent observers from 19 included studies. Data were pooled using a random-effects model with Comprehensive Meta-analysis software. Main Outcomes and Measures: Blood levels of BDNF in children with ASD compared with healthy controls. Altered levels of BDNF were hypothesized to be related to ASD. Results: This meta-analysis included 19 studies with 2896 unique participants. Random-effects meta-analysis of all 19 studies showed that children with ASD had significantly increased peripheral blood levels of BDNF compared with healthy controls (Hedges g, 0.490; 95% CI, 0.185-0.794; P = .002). Subgroup analyses in 4 studies revealed that neonates diagnosed with ASD later in life had no association with blood levels of BDNF (Hedges g, 0.384; 95% CI, -0.244 to 1.011; P = .23), whereas children in the nonneonate ASD group (15 studies) demonstrated significantly increased BDNF levels compared with healthy controls (Hedges g, 0.524; 95% CI, 0.206 to 0.842; P = .001). Further analysis showed that children in the nonneonate ASD group had increased BDNF levels in serum (10 studies) (Hedges g, 0.564; 95% CI, 0.168 to 0.960; P = .005) but not in plasma (5 studies) (Hedges g, 0.436; 95% CI, -0.176 to 1.048; P = .16). Meta-regression analyses revealed that sample size had a moderating effect on the outcome of the meta-analysis in the nonneonate group. In addition, no publication bias was found in the meta-analysis. Conclusions and Relevance: Children with ASD have increased peripheral blood levels of BDNF, strengthening the clinical evidence of an abnormal neurotrophic factor profile in this population.

From the genetic architecture to synaptic plasticity in autism spectrum disorder.

Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders.

Autism spectrum disorders (ASDs) and related neurological disorders are associated with mutations in many genes affecting the ratio between neuronal excitation and inhibition. However, understanding the impact of these mutations on network activity is complicated by the plasticity of these networks, making it difficult in many cases to separate initial deficits from homeostatic compensation. Here we explore the contrasting evidence for primary defects in inhibition or excitation in ASDs and attempt to integrate the findings in terms of the brain's ability to maintain functional homeostasis.

The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders.

Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials.

Neural targets in the study and treatment of social cognition in autism spectrum disorder.

The purpose of this chapter is to present results from recent research on social cognition in autism spectrum disorder (ASD). The clinical phenomenology and neuroanatomical circuitry of ASD are first briefly described. The neuropharmacology of social cognition in animal models of ASD and humans is then addressed. Next, preclinical and clinical research on the neurohormone oxytocin is reviewed. This is followed by a presentation of results from preclinical and clinical studies on the excitatory amino acid glutamate. Finally, the role of neuroinflammation in ASD is addressed from the perspectives of preclinical neuroscience and research involving humans with ASD.

CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder-related mutation.

Autism spectrum disorder (ASD) is a developmental brain disorder. Mutations in synaptic components including synaptic adhesion molecules have been found in ASD patients. Contactin-associated protein-like 2 (CASPR2) is one of the synaptic adhesion molecules associated with ASD. CASPR2 forms a complex with receptors via interaction with multiple PDZ domain protein 1 (MUPP1). Little is known about the relationship between impaired CASPR2-MUPP1-receptor complex and the pathogenesis of ASD. GPR37 is a receptor for survival factors. We recently identified mutations including R558Q in the G-protein-coupled receptor 37 (GPR37) gene in ASD patients. The mutated GPR37s accumulate in the endoplasmic reticulum. In this study, we show that GPR37 is a component of the CASPR2-MUPP1 receptor complex in the mouse brain. CASPR2 and GPR37 mainly interacted with the PDZ3 and PDZ11 domains of MUPP1, respectively. Compared to GPR37, GPR37(R558Q) slightly interacted with MUPP1 and caused dendritic alteration. GPR37, but not GPR37(R558Q) nor GPR37-deltaC which lacks its PDZ binding domain, was transported to the cell surface by MUPP1. In primary hippocampal neurons, GPR37 co-localized with MUPP1 and CASPR2 at the synapse, but not GPR37(R558Q). Thus, ASD-related mutation of GPR37 may cause the impaired CASPR2-MUPP1-GPR37 complex on the dendrites associated with one of the pathogenesis of ASD. In this study, we identified that GPR37 is a component of the MUPP1 and CASPR2 receptor complex. Autism deleterious mutated GPR37(R558Q) slightly interacts with MUPP1 and retains in ER, resulting in dendritic alteration. In neuron, GPR37, but not GPR37(R558Q), is transported to the dendrite and synapse by MUPP1. Thus, ASD-related mutation of GPR37 may cause the impaired CASPR2-MUPP1-GPR37 complex on the dendrites associated with one of the pathogenesis of ASD.

BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations.

A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult ß-hemoglobin: ß-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only BCL11A was commonly deleted in all of the patients. Evaluation of gene expression data sets from developing and adult human brains revealed that BCL11A expression patterns are similar to other genes associated with neurodevelopmental disorders. Additionally, common SNPs within the second intron of BCL11A are strongly associated with schizophrenia. Together, the study of these rare patients and orthogonal genetic data demonstrates that BCL11A plays a central role in silencing HbF in humans and implicates BCL11A as an important factor for neurodevelopment.

Controlling false discoveries in high-dimensional situations: boosting with stability selection.

BACKGROUND: Modern biotechnologies often result in high-dimensional data sets with many more variables than observations (n≪p). These data sets pose new challenges to statistical analysis: Variable selection becomes one of the most important tasks in this setting. Similar challenges arise if in modern data sets from observational studies, e.g., in ecology, where flexible, non-linear models are fitted to high-dimensional data. We assess the recently proposed flexible framework for variable selection called stability selection. By the use of resampling procedures, stability selection adds a finite sample error control to high-dimensional variable selection procedures such as Lasso or boosting. We consider the combination of boosting and stability selection and present results from a detailed simulation study that provide insights into the usefulness of this combination. The interpretation of the used error bounds is elaborated and insights for practical data analysis are given. RESULTS: Stability selection with boosting was able to detect influential predictors in high-dimensional settings while controlling the given error bound in various simulation scenarios. The dependence on various parameters such as the sample size, the number of truly influential variables or tuning parameters of the algorithm was investigated. The results were applied to investigate phenotype measurements in patients with autism spectrum disorders using a log-linear interaction model which was fitted by boosting. Stability selection identified five differentially expressed amino acid pathways. CONCLUSION: Stability selection is implemented in the freely available R package stabs (http://CRAN.R-project.org/package=stabs). It proved to work well in high-dimensional settings with more predictors than observations for both, linear and additive models. The original version of stability selection, which controls the per-family error rate, is quite conservative, though, this is much less the case for its improvement, complementary pairs stability selection. Nevertheless, care should be taken to appropriately specify the error bound.

Effects of trace metal profiles characteristic for autism on synapses in cultured neurons.

Various recent studies revealed that biometal dyshomeostasis plays a crucial role in the pathogenesis of neurological disorders such as autism spectrum disorders (ASD). Substantial evidence indicates that disrupted neuronal homeostasis of different metal ions such as Fe, Cu, Pb, Hg, Se, and Zn may mediate synaptic dysfunction and impair synapse formation and maturation. Here, we performed in vitro studies investigating the consequences of an imbalance of transition metals on glutamatergic synapses of hippocampal neurons. We analyzed whether an imbalance of any one metal ion alters cell health and synapse numbers. Moreover, we evaluated whether a biometal profile characteristic for ASD patients influences synapse formation, maturation, and composition regarding NMDA receptor subunits and Shank proteins. Our results show that an ASD like biometal profile leads to a reduction of NMDAR (NR/Grin/GluN) subunit 1 and 2a, as well as Shank gene expression along with a reduction of synapse density. Additionally, synaptic protein levels of GluN2a and Shanks are reduced. Although Zn supplementation is able to rescue the aforementioned alterations, Zn deficiency is not solely responsible as causative factor. Thus, we conclude that balancing Zn levels in ASD might be a prime target to normalize synaptic alterations caused by biometal dyshomeostasis.

The role of trace elements, thiamin (e) and transketolase in autism and autistic spectrum disorder.

Although there has been much research into autism or autistic spectrum disorder (ASD), there is room for considerable conjecture regarding the etiology of these developmental brain disorders. ASD is marked by a complex interaction between environmental factors and genetic predisposition, including epistasis. This manuscript argues that changes in oxidative metabolism, thiamine homeostasis, heavy metal deposition and cellular immunity have a role in the etiopathogenesis of autism and ASD. Recent findings from our group and others provide evidence for abnormal thiol metabolism, marked by significant alteration in the deposition of several trace heavy metal species. Together with these, we find differences in thiamine homeostasis in ASD patients, which can be corrected by supplementation. We hypothesize that altered thiol metabolism from heavy metal toxicity, one of the key mechanisms for oxidative stress production, may be responsible for the biochemical alterations in transketolase, dysautonomia and abnormal thiamine homeostasis. Although it is unknown why these particular metals accumulate, we suspect that children with ASD and forms of autism may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. We maintain mercury accumulation is evidence of altered clearance. Together with concomitant oxidative stress, these findings may offer an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Regardless of the exact cause, these factors may be more important to the etiology of this symptomatically diverse disease spectrum. Here, we offer insight into new avenues of exploration as well as the development of novel treatment approaches for these growing and devastating diseases.

Autism spectrum disorder: an omics perspective.

Current directions in autism spectrum disorder (ASD) research may require moving beyond genetic analysis alone, based on the complexity of the disorder, heterogeneity and convergence of genetic alterations at the cellular/functional level. Mass spectrometry (MS) has been increasingly used to study CNS disorders, including ASDs. Proteomic research using MS is directed at understanding endogenous protein changes that occur in ASD. This review focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using MS, including fragile X syndrome (FXS) and Smith-Lemli-Opitz Syndrome (SLOS), genetic syndromes highly associated with ASD comorbidity.

Autism biomarkers: challenges, pitfalls and possibilities.

Network perspectives, in their emphasis on components and their interactions, might afford the best approach to the complexities of the ASD realm. Categorical approaches are unlikely to be fruitful as one should not expect to find a single or even predominant underlying cause of autism behavior across individuals. It is possible that the complex, highly interactive, heterogeneous and individualistic nature of the autism realm is intractable in terms of identifying clinically useful biomarker tests. It is hopeful from an emergenic perspective that small corrective changes in a single component of a deleterious network/configuration might have large beneficial consequences on developmental trajectories and in later treatment. It is suggested that the relationship between ASD and intellectual disability might be fundamentally different in single-gene versus nonsyndromic ASD. It is strongly stated that available biomarker "tests" for autism/ASD will do more harm than good. Finally, the serotonin-melatonin-oxidative stress-placental intersection might be an especially fruitful area of biological investigation.

Action control processes in autism spectrum disorder--insights from a neurobiological and neuroanatomical perspective.

Autism spectrum disorders (ASDs) encompass a range of syndromes that are characterized by social interaction impairments, verbal and nonverbal communication difficulties, and stereotypic or repetitive behaviours. Although there has been considerable progress in understanding the mechanisms underlying the changes in the 'social' and 'communicative' aspects of ASD, the neurofunctional architecture of repetitive and stereotypic behaviours, as well as other cognitive domains related to response and action control, remain poorly understood. Based on the findings of neurobiological and neuroanatomical alterations in ASD and the functional neuroanatomy and neurobiology of different action control functions, we emphasize that changes in action control processes, including response inhibition, conflict and response monitoring, task switching, dual-tasking, motor timing, and error monitoring, are important facets of ASD. These processes must be examined further to understand the executive control deficits in ASD that are related to stereotypic or repetitive behaviours as a major facet of ASD. The review shows that not all domains of action control are strongly affected in ASD. Several factors seem to determine the consistency with which alterations in cognitive control are reported. These factors relate to the relevance of neurobiological changes in ASD for the cognitive domains examined and in how far action control relies upon the adjustment of prior experience. Future directions and hypotheses are outlined that may guide basic and clinical research on action control in ASD.

Clinical and pharmacokinetic evaluation of risperidone for the management of autism spectrum disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is often accompanied by psychiatric comorbidity. Although there is no medication currently available to treat the core symptoms of ASD, risperidone was the first drug to be approved for use in ASD and is still the best established psychopharmacological option for the treatment of irritability and behavioral problems in ASD. AREAS COVERED: This article gives an overview of the pharmacokinetic profile of risperidone and a comprehensive review of treatment studies regarding the use of risperidone in ASD. EXPERT OPINION: Ample evidence supports the short-term use of risperidone for treating irritability and behavioral problems in ASD. Risperidone also shows promise in treating symptoms often associated with ASD, such as stereotypical behavior, social difficulties, hyperactivity and cognitive problems. However, several adverse effects have been identified; most are mild or moderate and well manageable, but weight gain and metabolic changes are a considerable concern. Therefore, risperidone should in our view be seen as 'a last resort', only justified for the short-term treatment of serious behavioral problems, which have failed to respond sufficiently to behavioral interventions. Future studies should investigate long-term effects of risperidone and factors that facilitate individual risk-benefit analyses before treatment.

Successful face recognition is associated with increased prefrontal cortex activation in autism spectrum disorder.

This study examines whether deficits in visual information processing in autism-spectrum disorder (ASD) can be offset by the recruitment of brain structures involved in selective attention. During functional MRI, 12 children with ASD and 19 control participants completed a selective attention one-back task in which images of faces and houses were superimposed. When attending to faces, the ASD group showed increased activation relative to control participants within multiple prefrontal cortex areas, including dorsolateral prefrontal cortex (DLPFC). DLPFC activation in ASD was associated with increased response times for faces. These data suggest that prefrontal cortex activation may represent a compensatory mechanism for diminished visual information processing abilities in ASD.