Proteomic Investigations of Autism Brain Identify Known and Novel Pathogenetic Processes

Abstract Autism Spectrum Disorder (ASD) is a set of heterogeneous neurodevelopmental conditions defined by impairments in social communication and restricted, repetitive behaviors, interests or activities. Only a minority of ASD cases are determined to have a definitive etiology and the pathogenesis of most ASD is poorly understood. We hypothesized that a global analysis of the proteomes of human ASD vs. control brain, heretofore not done, would provide important data with which to better understand the underlying neurobiology of autism. In this study, we characterized the proteomes of two brain regions, Brodmann area 19 (BA19) and posterior inferior cerebellum (CB), from carefully selected idiopathic ASD cases and matched controls using label-free HPLC-tandem mass spectrometry. The data revealed marked differences between ASD and control brain proteomes for both brain regions. Unlike earlier transcriptomic analyses using frontal and temporal cortex, however, our proteomic analysis did not support ASD attenuating regional gene expression differences. Bioinformatic analyses of the differentially expressed proteins between cases and controls highlighted canonical pathways involving glutamate receptor signaling and glutathione-mediated detoxification in both BA19 and CB; other pathways such as Sertoli cell signaling and fatty acid oxidation were specifically enriched in BA19 or CB, respectively. Network analysis of both regions of ASD brain showed up-regulation of multiple pre- and post-synaptic membrane or scaffolding proteins including glutamatergic ion channels and related proteins, up-regulation of proteins involved in intracellular calcium signaling, and down-regulation of neurofilament proteins, with DLG4 and MAPT as major hub proteins in BA19 and CB protein interaction networks, respectively. Upstream regulator analysis suggests neurodegeneration-associated proteins drive the differential protein expression for ASD in both BA19 and CB. Overall, the proteomic data provide support for shared dysregulated pathways and upstream regulators for two brain regions in human ASD brain, suggesting a common ASD pathophysiology that has distinctive regional expression.

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Distributed networks for auditory memory contribute differentially to recall precision

10.1101/2021.01.18.427143 ◽

2021 ◽

Author(s):

Sung-Joo Lim ◽

Christiane Thiel ◽

Bernhard Sehm ◽

Lorenz Deserno ◽

Jöran Lepsien ◽

...

Keyword(s):

Working Memory ◽

Cognitive Control ◽

Brain Networks ◽

Temporal Cortex ◽

Superior Temporal Sulcus ◽

Brain Regions ◽

Auditory Memory ◽

Control Brain ◽

Memory Representations ◽

Auditory Objects

AbstractThe representations held in working memory are inherently noisy, but attention directed to relevant objects can effectively enhance their fidelity. While recent working memory models suggest that memory representations are distributed across sensory and cognitive-control brain regions, it remains unknown how multiple brain networks generate this attentional gain in fidelity. Here, we investigated the contributions of the distinct brain networks in maintaining and enhancing memory representations using psychophysical modeling and fMRI. Human listeners performed an auditory syllable pitch-discrimination task, in which they received valid (vs. neutral) retro-active cues to selectively attend to one of the two syllable categories maintained in memory. Valid (vs. neutral) retro-cues facilitated task performance, eliciting faster recall and enhanced recall precision of syllables in memory. Valid retro-cues also led to increased neural activation in fronto-parietal and cingulo-opercular networks, but not in sensory-specific superior temporal cortex. Multivariate pattern analysis as a proxy for representational fidelity in memory revealed that attended syllable objects were maintained in distributed areas across superior temporal, frontal, parietal, and sensorimotor brain areas. However, neural fidelity in left superior temporal sulcus and its enhancement through attention-to-memory best predicted the ensuing individual gain in recall precision of auditory objects from memory. These results demonstrate that maintaining versus attentionally enhancing auditory memory representations are functionally separable mechanisms across distributed brain regions.Significance StatementWorking memory is distributed across sensory and cognitive-control brain regions. But how do these brain networks enhance working memory precision when attention is re-directed to memory? We here investigate the contributions of distinct brain networks in maintaining and enhancing auditory memory representations through attention-to-memory using fMRI. We demonstrate that re-directing attention to the relevant auditory memory objects mainly recruits higher-order cognitive-control networks. Among the multiple brain regions retaining memory representations, however, attentional enhancement of the neural fidelity in superior temporal sulcus best predicts the individual gain in recall precision of auditory objects from memory. This study provides evidence of the interplay among the discrete, functionally specialized brain regions in maintaining and attentionally enhancing working memory representations.

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Role of Oligodendrocytes and Myelin in the Pathophysiology of Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci10120951 ◽

2020 ◽

Vol 10 (12) ◽

pp. 951

Author(s):

Alma Y. Galvez-Contreras ◽

David Zarate-Lopez ◽

Ana L. Torres-Chavez ◽

Oscar Gonzalez-Perez

Keyword(s):

Autism Spectrum Disorder ◽

Interpersonal Communication ◽

Neurodevelopmental Disorder ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Abnormal Development ◽

Matter Production

Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.

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Longitudinal Changes in Cortical Thickness in Adolescents with Autism Spectrum Disorder and Their Association with Restricted and Repetitive Behaviors

Genes ◽

10.3390/genes12122024 ◽

2021 ◽

Vol 12 (12) ◽

pp. 2024

Author(s):

Valentina Bieneck ◽

Anke Bletsch ◽

Caroline Mann ◽

Tim Schäfer ◽

Hanna Seelemeyer ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Individual Differences ◽

Cortical Thickness ◽

Brain Regions ◽

Autism Spectrum ◽

Developmental Trajectory ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Childhood And Adolescence ◽

Autism Symptoms

The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes.

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Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

Human Molecular Genetics ◽

10.1093/hmg/ddz052 ◽

2019 ◽

Vol 28 (13) ◽

pp. 2201-2211 ◽

Cited By ~ 17

Author(s):

Chloe C Y Wong ◽

Rebecca G Smith ◽

Eilis Hannon ◽

Gokul Ramaswami ◽

Neelroop N Parikshak ◽

...

Keyword(s):

Dna Methylation ◽

Temporal Cortex ◽

Brain Regions ◽

Autism Spectrum ◽

Genomic Variation ◽

Molecular Signatures ◽

Post Mortem ◽

Human Brain Tissue ◽

Genome Wide ◽

Syndromic Autism

Abstract Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

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Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic forms of autism in post-mortem human brain tissue

10.1101/394387 ◽

2018 ◽

Cited By ~ 2

Author(s):

Chloe C.Y. Wong ◽

Rebecca G. Smith ◽

Eilis Hannon ◽

Gokul Ramaswami ◽

Neelroop N. Parikshak ◽

...

Keyword(s):

Dna Methylation ◽

Temporal Cortex ◽

Brain Regions ◽

Autism Spectrum ◽

Genomic Variation ◽

Molecular Signatures ◽

Post Mortem ◽

Human Brain Tissue ◽

Systematic Analysis ◽

Genome Wide

AbstractAutism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behavior. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular etiology of ASD, we quantified genome-wide patterns of DNA methylation in 233 post-mortem tissues samples isolated from three brain regions (prefrontal cortex, temporal cortex and cerebellum) dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the cerebellum. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically-defined subtype of ASD, were characterized by striking differences in DNA methylation across a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.

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Autistic Spectrum Disorder Detection and Structural Biomarker Identification Using Self-Attention Model and Individual-Level Morphological Covariance Brain Networks

Frontiers in Neuroscience ◽

10.3389/fnins.2021.756868 ◽

2021 ◽

Vol 15 ◽

Author(s):

Zhengning Wang ◽

Dawei Peng ◽

Yongbin Shang ◽

Jingjing Gao

Keyword(s):

Deep Learning ◽

Structural Model ◽

Temporal Cortex ◽

Brain Regions ◽

Autism Spectrum ◽

Brain Network ◽

The Self ◽

Spectrum Disorder ◽

Learning Framework ◽

Transformer Model

Autism spectrum disorder (ASD) is a range of neurodevelopmental disorders, which brings enormous burdens to the families of patients and society. However, due to the lack of representation of variance for diseases and the absence of biomarkers for diagnosis, the early detection and intervention of ASD are remarkably challenging. In this study, we proposed a self-attention deep learning framework based on the transformer model on structural MR images from the ABIDE consortium to classify ASD patients from normal controls and simultaneously identify the structural biomarkers. In our work, the individual structural covariance networks are used to perform ASD/NC classification via a self-attention deep learning framework, instead of the original structural MR data, to take full advantage of the coordination patterns of morphological features between brain regions. The self-attention deep learning framework based on the transformer model can extract both local and global information from the input data, making it more suitable for the brain network data than the CNN- structural model. Meanwhile, the potential diagnosis structural biomarkers are identified by the self-attention coefficients map. The experimental results showed that our proposed method outperforms most of the current methods for classifying ASD patients with the ABIDE data and achieves a classification accuracy of 72.5% across different sites. Furthermore, the potential diagnosis biomarkers were found mainly located in the prefrontal cortex, temporal cortex, and cerebellum, which may be treated as the early biomarkers for the ASD diagnosis. Our study demonstrated that the self-attention deep learning framework is an effective way to diagnose ASD and establish the potential biomarkers for ASD.

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Transcriptional subtyping explains phenotypic variability in genetic subtypes of autism spectrum disorder

Development and Psychopathology ◽

10.1017/s0954579420000784 ◽

2020 ◽

Vol 32 (4) ◽

pp. 1353-1361

Author(s):

Sandy Trinh ◽

Anne Arnett ◽

Evangeline Kurtz-Nelson ◽

Jennifer Beighley ◽

Marta Picoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Communication ◽

Phenotypic Variability ◽

Expression Patterns ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Phenotypic Heterogeneity ◽

Spectrum Disorder ◽

Genetic Subtypes

AbstractAutism spectrum disorder (ASD) is a common neurodevelopmental disorder characterized by deficits in social communication and presence of restricted, repetitive behaviors, and interests. However, individuals with ASD vary significantly in their challenges and abilities in these and other developmental domains. Gene discovery in ASD has accelerated in the past decade, and genetic subtyping has yielded preliminary evidence of utility in parsing phenotypic heterogeneity through genomic subtypes. Recent advances in transcriptomics have provided additional dimensions with which to refine genetic subtyping efforts. In the current study, we investigate phenotypic differences among transcriptional subtypes defined by neurobiological spatiotemporal co-expression patterns. Of the four transcriptional subtypes examined, participants with mutations to genes typically expressed highly in all brain regions prenatally, and those with differential postnatal cerebellar expression relative to other brain regions, showed lower cognitive and adaptive skills, higher severity of social communication deficits, and later acquisition of speech and motor milestones, compared to those with mutations to genes highly expressed during the postnatal period across brain regions. These findings suggest higher-order characterization of genetic subtypes based on neurobiological expression patterns may be a promising approach to parsing phenotypic heterogeneity among those with ASD and related neurodevelopmental disorders.

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The Parvalbumin Hypothesis of Autism Spectrum Disorder

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.577525 ◽

2020 ◽

Vol 14 ◽

Author(s):

Federica Filice ◽

Lucia Janickova ◽

Thomas Henzi ◽

Alessandro Bilella ◽

Beat Schwaller

Keyword(s):

Autism Spectrum Disorder ◽

Messenger Rna ◽

Energy Requirement ◽

Neurodevelopmental Disorder ◽

High Energy ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Supporting Evidence

The prevalence of autism spectrum disorder (ASD)—a type of neurodevelopmental disorder—is increasing and is around 2% in North America, Asia, and Europe. Besides the known genetic link, environmental, epigenetic, and metabolic factors have been implicated in ASD etiology. Although highly heterogeneous at the behavioral level, ASD comprises a set of core symptoms including impaired communication and social interaction skills as well as stereotyped and repetitive behaviors. This has led to the suggestion that a large part of the ASD phenotype is caused by changes in a few and common set of signaling pathways, the identification of which is a fundamental aim of autism research. Using advanced bioinformatics tools and the abundantly available genetic data, it is possible to classify the large number of ASD-associated genes according to cellular function and pathways. Cellular processes known to be impaired in ASD include gene regulation, synaptic transmission affecting the excitation/inhibition balance, neuronal Ca2+ signaling, development of short-/long-range connectivity (circuits and networks), and mitochondrial function. Such alterations often occur during early postnatal neurodevelopment. Among the neurons most affected in ASD as well as in schizophrenia are those expressing the Ca2+-binding protein parvalbumin (PV). These mainly inhibitory interneurons present in many different brain regions in humans and rodents are characterized by rapid, non-adaptive firing and have a high energy requirement. PV expression is often reduced at both messenger RNA (mRNA) and protein levels in human ASD brain samples and mouse ASD (and schizophrenia) models. Although the human PVALB gene is not a high-ranking susceptibility/risk gene for either disorder and is currently only listed in the SFARI Gene Archive, we propose and present supporting evidence for the Parvalbumin Hypothesis, which posits that decreased PV level is causally related to the etiology of ASD (and possibly schizophrenia).

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Maternal SSRI treatment during offspring development results in long-term behavioral, cellular, and neuroimaging disruptions

10.1101/205708 ◽

2017 ◽

Author(s):

Susan E. Maloney ◽

Rachel Rahn ◽

Shyam Akula ◽

Michael A. Rieger ◽

Katherine B. McCullough ◽

...

Keyword(s):

Drug Exposure ◽

Epidemiological Studies ◽

Brain Regions ◽

Autism Spectrum ◽

Dendritic Morphology ◽

Repetitive Behaviors ◽

Intrinsic Signal ◽

Optical Intrinsic Signal ◽

Ssri Treatment

SummarySerotonergic dysregulation is implicated in psychiatric disorders, including autism spectrum disorders (ASD). Epidemiological studies suggest selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy may increase ASD risk in offspring, however it is unclear from these studies whether ASD susceptibility is related to the maternal diagnosis or if treatment poses additional risk. Here, we exposed mouse dams to fluoxetine and characterized the offspring to isolate possible effects of SSRI exposure on ASD-relevant behaviors. We demonstrate social communication and interaction deficits and repetitive behaviors, with corresponding dendritic morphology changes in pertinent brain regions. Also, using a novel application of optical intrinsic signal imaging, we show altered stimulus-evoked cortical response and region-specific decreases in functional connectivity. These findings indicate drug exposure alone is sufficient to induce long-term behavioral, cellular, and hemodynamic-response disruptions in offspring, thus contributing to our understanding of ASD pathogenesis, risk and mechanism, as well as the developmental role of serotonin.

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Neurobiological Abnormalities in the First Few Years of Life in Individuals Later Diagnosed with Autism Spectrum Disorder: A Review of Recent Data

Behavioural Neurology ◽

10.1155/2014/210780 ◽

2014 ◽

Vol 2014 ◽

pp. 1-20 ◽

Cited By ~ 12

Author(s):

C. S. Allely ◽

C. Gillberg ◽

P. Wilson

Keyword(s):

Autism Spectrum Disorder ◽

Language Processing ◽

Temporal Cortex ◽

Brain Regions ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Sequence Of Events ◽

Neurological Abnormalities ◽

Functional Development ◽

First Year Of Life

Background. Despite the widely-held understanding that the biological changes that lead to autism usually occur during prenatal life, there has been relatively little research into the functional development of the brain during early infancy in individuals later diagnosed with autism spectrum disorder (ASD).Objective. This review explores the studies over the last three years which have investigated differences in various brain regions in individuals with ASD or who later go on to receive a diagnosis of ASD.Methods. We used PRISMA guidelines and selected published articles reporting any neurological abnormalities in very early childhood in individuals with or later diagnosed with ASD.Results. Various brain regions are discussed including the amygdala, cerebellum, frontal cortex, and lateralised abnormalities of the temporal cortex during language processing. This review discusses studies investigating head circumference, electrophysiological markers, and interhemispheric synchronisation. All of the recent findings from the beginning of 2009 across these different aspects of defining neurological abnormalities are discussed in light of earlier findings.Conclusions. The studies across these different areas reveal the existence of atypicalities in the first year of life, well before ASD is reliably diagnosed. Cross-disciplinary approaches are essential to elucidate the pathophysiological sequence of events that lead to ASD.

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