Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug target for epilepsy ...and neuropathic pain; thus the TSP-α2δ-1 interaction is implicated in both synaptic development and disease pathogenesis. However, the mechanism by which this interaction promotes synaptogenesis and the requirement for α2δ-1 for connectivity of the developing mammalian brain are unknown. In this study, we show that global or cell-specific loss of α2δ-1 yields profound deficits in excitatory synapse numbers, ultrastructure, and activity and severely stunts spinogenesis in the mouse cortex. Postsynaptic but not presynaptic α2δ-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo, but an α2δ-1 mutant linked to autism cannot rescue these synaptogenesis defects. Finally, we reveal that TSP-α2δ-1 interactions control synaptogenesis postsynaptically via Rac1, suggesting potential molecular mechanisms that underlie both synaptic development and pathology.
The gut microbiota has become a focus of research for those interested in the brain and behaviour. Here, we profile the gut microbiota in a variety of neuropsychiatric syndromes.
Multiple routes of ...communication between the gut and brain have been established and these include the vagus nerve, immune system, short chain fatty acids and tryptophan. Developmentally, those born by caesarean section have a distinctly different microbiota in early life to those born per vaginum. At the other extreme, individuals who age with considerable ill-heath tend to show narrowing in microbial diversity. Recently, the gut microbiota has been profiled in a variety of conditions including autism, major depression and Parkinson's disease. There is still debate as to whether or not these changes are core to the pathophysiology or merely epiphenomenal.
The current narrative suggests that certain neuropsychiatric disorders might be treated by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics.
Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the ...potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the
Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders.
Cntnap2
−/−
mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with
CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for
CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.
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► The
Cntnap2
−/−
mouse model of ASD shows striking parallels with the human disease ► CNTNAP2 affects the development of neuronal circuits, including GABAergic neurons ► Our results support a role for neuronal synchrony in the pathophysiology of ASD ► This model permits dissociation of the circuitries involved in ASD core behaviors
Existing mouse models of autism often fail to capture important aspects of human disease. Mice lacking expression of a neurexin exhibit striking parallels with autism spectrum disorders, recapitulating the key behaviors, neuroanatomical defects, and pharmacological responses of human patients.
Microarray methodologies, including array comparative genomic hybridization and single-nucleotide polymorphism–detecting arrays, are accepted as an appropriate first-tier test for the evaluation of ...imbalances associated with intellectual disability, autism, and multiple congenital anomalies. This technology also has applicability in prenatal specimens. To assist clinical laboratories in validation of microarray methodologies for constitutional applications, the American College of Medical Genetics and Genomics has produced the following revised professional standards and guidelines.
The interpersonal distance (IPD) theory provides a novel approach to studying autism spectrum disorder (ASD). In this article, we present recent findings on the neurobiological underpinnings of IPD ...regulation that are distinct in individuals with ASD. We also discuss the potential influence of environmental factors on IPD. We suggest that different IPD regulation may have implications for cognitive performance in experimental and diagnostic settings, may influence the effectiveness of training and therapy, and may play a role in the typical forms of social communication and leisure activities chosen by autistic individuals. We argue that reconsidering the results of ASD research through the lens of IPD would lead to a different interpretation of previous findings. Finally, we propose a methodological approach to study this phenomenon systematically.
Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by social deficits and stereotyped behaviors. While several theories have emerged, the pathogenesis of ...ASD remains unknown. Although studies report dopamine signaling abnormalities in autistic patients, a coherent dopamine hypothesis which could link neurobiology to behavior in ASD is currently lacking. In this paper, we present such a hypothesis by proposing that autistic behavior arises from dysfunctions in the midbrain dopaminergic system. We hypothesize that a dysfunction of the mesocorticolimbic circuit leads to social deficits, while a dysfunction of the nigrostriatal circuit leads to stereotyped behaviors. Furthermore, we discuss 2 key predictions of our hypothesis, with emphasis on clinical and therapeutic aspects. First, we argue that dopaminergic dysfunctions in the same circuits should associate with autistic-like behavior in nonautistic subjects. Concerning this, we discuss the case of PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections) which displays behaviors similar to those of ASD, presumed to arise from dopaminergic dysfunctions. Second, we argue that providing dopamine modulators to autistic subjects should lead to a behavioral improvement. Regarding this, we present clinical studies of dopamine antagonists which seem to have improving effects on autistic behavior. Furthermore, we explore the means of testing our hypothesis by using neuroreceptor imaging, which could provide comprehensive evidence for dopamine signaling dysfunctions in autistic subjects. Lastly, we discuss the limitations of our hypothesis. Along these lines, we aim to provide a dopaminergic model of ASD which might lead to a better understanding of the ASD pathogenesis.
Parents of children with developmental disabilities, particularly autism spectrum disorders (ASDs), are at risk for high levels of distress. The factors contributing to this are unclear. This study ...investigated how child characteristics influence maternal parenting stress and psychological distress. Participants consisted of mothers and developmental-age matched preschool-aged children with ASD (N = 51) and developmental delay without autism (DD) ( N = 22). Evidence for higher levels of parenting stress and psychological distress was found in mothers in the ASD group compared to the DD group. Children's problem behavior was associated with increased parenting stress and psychological distress in mothers in the ASD and DD groups. This relationship was stronger in the DD group. Daily living skills were not related to parenting stress or psychological distress. Results suggest clinical services aiming to support parents should include a focus on reducing problem behaviors in children with developmental disabilities.
Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity ...in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of “cortical separation distances” to assess the global and local intrinsic “wiring costs” of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical “connectivity” in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms.
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•Novel procedure to identify significant genetic differences between autism subgroups.•Data mining techniques allow testing of combinations of genes.•Data-driven procedure for SNP ...prioritization reduces experimental bias.•286 genes associated with specific autism subgroups – 193 novel autism candidates.
Though the genetic etiology of autism is complex, our understanding can be improved by identifying genes and gene-gene interactions that contribute to the development of specific autism subtypes. Identifying such gene groupings will allow individuals to be diagnosed and treated according to their precise characteristics. To this end, we developed a method to associate gene combinations with groups with shared autism traits, targeting genetic elements that distinguish patient populations with opposing phenotypes. Our computational method prioritizes genetic variants for genome-wide association, then utilizes Frequent Pattern Mining to highlight potential interactions between variants. We introduce a novel genotype assessment metric, the Unique Inherited Combination support, which accounts for inheritance patterns observed in the nuclear family while estimating the impact of genetic variation on phenotype manifestation at the individual level. High-contrast variant combinations are tested for significant subgroup associations. We apply this method by contrasting autism subgroups defined by severe or mild manifestations of a phenotype. Significant associations connected 286 genes to the subgroups, including 193 novel autism candidates. 71 pairs of genes have joint associations with subgroups, presenting opportunities to investigate interacting functions. This study analyzed 12 autism subgroups, but our informatics method can explore other meaningful divisions of autism patients, and can further be applied to reveal precise genetic associations within other phenotypically heterogeneous disorders, such as Alzheimer’s disease.
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