Outside-in: Rethinking the etiology of autism spectrum disorders

Orefice, Lauren L.

doi:10.1126/science.aaz3880

Cited by 12 publications

(12 citation statements)

References 19 publications

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“…Autism spectrum disorder (ASD) is a neurodevelopmental disorder, the core symptoms of which are difficulties in social interaction and communication, narrow interests, and repetitive behaviors. Current etiological studies believe that ASD is a complex mental illness with high heritability and etiological heterogeneity [1]. ASD was reported as a multi-system disorder involving genetics, immunogenetics, immunology, microbiology, metabolic, and so on [2].…”

Section: Introductionmentioning

confidence: 99%

Gene Module Analysis Reveals Cell-Type Specificity and Potential Target Genes in Autism’s Pathogenesis

et al. 2021

Biomedicines

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Multiple genetic factors contribute to the pathogenesis of autism spectrum disorder (ASD), a kind of neurodevelopmental disorder. Genes were usually studied separately for their associations with ASD. However, genes associated with ASD do not act alone but interact with each other in a network module. The identification of these modules is the basis for the systematic understanding of the pathogenesis of ASD. Moreover, ASD is characterized by highly pathogenic heterogeneity, and gene modules associated with ASD are cell-type-specific. In this study, based on the single-nucleus RNA sequencing data of 41 post-mortem tissue samples from the prefrontal cortex and anterior cingulate cortex of 19 ASD patients and 16 control individuals, we applied sparse module activity factorization, a matrix decomposition method consistent with the multi-factor and heterogeneous characteristics of ASD pathogenesis, to identify cell-type-specific gene modules. Then, statistical procedures were performed to detect highly reproducible cell-type-specific ASD-associated gene modules. Through the enrichment analysis of cell markers, 31 cell-type-specific gene modules related to ASD were further screened out. These 31 gene modules are all enriched with curated ASD risk genes. Finally, we utilized the expression patterns of these cell-type-specific ASD-associated gene modules to build predictive models for ASD. The excellent predictive performance also proved the associations between these gene modules and ASD. Our study confirmed the multifactorial and cell-type-specific characteristics of ASD pathogeneses. The results showed that excitatory neurons such as L2/3, L4, and L5/6-CC play essential roles in ASD’s pathogenic processes. We identified the potential ASD target genes that act together in cell-type-specific modules, such as NRG3, KCNIP4, BAI3, PTPRD, LRRTM4, and LINGO2 in the L2/3 gene modules. Our study offers new potential genomic targets for ASD and provides a novel method to study gene modules involved in the pathogenesis of ASD.

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Section: Introductionmentioning

confidence: 99%

Gene Module Analysis Reveals Cell-Type Specificity and Potential Target Genes in Autism’s Pathogenesis

et al. 2021

Biomedicines

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“…Many studies conducted in rodent models of ASD with highly penetrant monogenic mutations, indicate that abnormalities in sensory reactivity correlate with ASD-related phenotypes, in line with the hypothesis that impaired sensory perception may impact brain development and function, and results in disparate symptoms associated with ASD [39]. This hypothesis provides a potential mechanistic link between otherwise heterogeneous ASD-related phenotypes, and implicates peripheral sensory neurons, in addition to the other neuronal types discussed above, in ASD etiology [40].…”

Section: Cell Types Of Both Developing and Adult Brain Are Vulnerablementioning

confidence: 60%

Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets

2021

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Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by impaired social interactions as well as the presentation of restrictive and repetitive behaviors. ASD is highly heritable but genetically heterogenous with both common and rare genetic variants collaborating to predispose individuals to the disorder. In this review, we synthesize recent efforts to develop human induced pluripotent stem cell (iPSC)-derived models of ASD-related phenotypes. We firstly address concerns regarding the relevance and validity of available neuronal iPSC-derived models. We then critically evaluate the robustness of various differentiation and cell culture protocols used for producing cell types of relevance to ASD. By exploring iPSC models of ASD reported thus far, we examine to what extent cellular and neuronal phenotypes with potential relevance to ASD can be linked to genetic variants found to underlie it. Lastly, we outline promising strategies by which iPSC technology can both enhance the power of genetic studies to identify ASD risk factors and nominate pathways that are disrupted across groups of ASD patients that might serve as common points for therapeutic intervention.

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“…Autism spectrum disorder (ASD) is defined by persistent deficits in the ability to initiate and to sustain reciprocal social interaction and social communication and characterized by a range of restricted, repetitive, and inflexible patterns of behavior, as well as various sensory abnormalities (1)(2)(3)(4)(5). SHANK3 is a scaffolding protein located at excitatory synapses, and mutations of SHANK3 (haploinsufficiency) may account for 1-2% of all ASD cases including Phelan-McDermid syndrome (PMS) (2,6,7).…”

Section: Introductionmentioning

confidence: 99%

SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis

Zhang

Bang²,

He³

et al. 2023

Front. Immunol.

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Excessive inflammation has been implicated in autism spectrum disorder (ASD), but the underlying mechanisms have not been fully studied. SHANK3 is a synaptic scaffolding protein and mutations of SHANK3 are involved in ASD. Shank3 expression in dorsal root ganglion sensory neurons also regulates heat pain and touch. However, the role of Shank3 in the vagus system remains unknown. We induced systemic inflammation by lipopolysaccharide (LPS) and measured body temperature and serum IL-6 levels in mice. We found that homozygous and heterozygous Shank3 deficiency, but not Shank2 and Trpv1 deficiency, aggravates hypothermia, systemic inflammation (serum IL-6 levels), and sepsis mortality in mice, induced by lipopolysaccharide (LPS). Furthermore, these deficits can be recapitulated by specific deletion of Shank3 in Nav1.8-expressing sensory neurons in conditional knockout (CKO) mice or by selective knockdown of Shank3 or Trpm2 in vagal sensory neurons in nodose ganglion (NG). Mice with Shank3 deficiency have normal basal core temperature but fail to adjust body temperature after perturbations with lower or higher body temperatures or auricular vagus nerve stimulation. In situ hybridization with RNAscope revealed that Shank3 is broadly expressed by vagal sensory neurons and this expression was largely lost in Shank3 cKO mice. Mechanistically, Shank3 regulates the expression of Trpm2 in NG, as Trpm2 but not Trpv1 mRNA levels in NG were significantly reduced in Shank3 KO mice. Our findings demonstrated a novel molecular mechanism by which Shank3 in vagal sensory neurons regulates body temperature, inflammation, and sepsis. We also provided new insights into inflammation dysregulation in ASD.

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Outside-in: Rethinking the etiology of autism spectrum disorders

Abstract: Transverse section of a mouse dorsal root ganglion (DRG), showing neurons transduced with a virus expressing the b3 subunit of the GABA A receptor (green), NF200 expression in large-diameter DRG neurons (yellow), and Hoechst (blue).

Cited by 12 publications

References 19 publications

Gene Module Analysis Reveals Cell-Type Specificity and Potential Target Genes in Autism’s Pathogenesis

Gene Module Analysis Reveals Cell-Type Specificity and Potential Target Genes in Autism’s Pathogenesis

Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets

SHANK3 in vagal sensory neurons regulates body temperature, systemic inflammation, and sepsis

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