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Functional and molecular characterization of a non-human primate model of autism spectrum disorder shows similarity with the human disease.

ABSTRACT: Autism spectrum disorder (ASD) is a multifactorial disorder with characteristic synaptic and gene expression changes. Early intervention during childhood is thought to benefit prognosis. Here, we examined the changes in cortical synaptogenesis, synaptic function, and gene expression from birth to the juvenile stage in a marmoset model of ASD induced by valproic acid (VPA) treatment. Early postnatally, synaptogenesis was reduced in this model, while juvenile-age VPA-treated marmosets showed increased synaptogenesis, similar to observations in human tissue. During infancy, synaptic plasticity transiently increased and was associated with altered vocalization. Synaptogenesis-related genes were downregulated early postnatally. At three months of age, the differentially expressed genes were associated with circuit remodeling, similar to the expression changes observed in humans. In summary, we provide a functional and molecular characterization of a non-human primate model of ASD, highlighting its similarity to features observed in human ASD.

SUBMITTER: Watanabe S

PROVIDER: S-EPMC8443557 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Functional and molecular characterization of a non-human primate model of autism spectrum disorder shows similarity with the human disease.

Watanabe Satoshi S Kurotani Tohru T Oga Tomofumi T Noguchi Jun J Isoda Risa R Nakagami Akiko A Sakai Kazuhisa K Nakagaki Keiko K Sumida Kayo K Hoshino Kohei K Saito Koichi K Miyawaki Izuru I Sekiguchi Masayuki M Wada Keiji K Minamimoto Takafumi T Ichinohe Noritaka N

Nature communications 20210915 1

Autism spectrum disorder (ASD) is a multifactorial disorder with characteristic synaptic and gene expression changes. Early intervention during childhood is thought to benefit prognosis. Here, we examined the changes in cortical synaptogenesis, synaptic function, and gene expression from birth to the juvenile stage in a marmoset model of ASD induced by valproic acid (VPA) treatment. Early postnatally, synaptogenesis was reduced in this model, while juvenile-age VPA-treated marmosets showed incre ...[more]

PMID: 34526497

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Project description:Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with clinical presentation and prognostic heterogeneity. Ferroptosis is a regulated non-apoptotic cell death program implicated in the occurrence and progression of various diseases. Therefore, we aimed to explore ferroptosis-related molecular subtypes in ASD and further illustrate the potential mechanism. Methods: A total of 201 normal samples and 293 ASD samples were obtained from the Gene Expression Omnibus (GEO) database. We used the unsupervised clustering analysis to identify the molecular subtypes based on ferroptosis-related genes (FRGs) and evaluate the immune characteristics between ferroptosis subtypes. Ferroptosis signatures were identified using the least absolute shrinkage and selection operator regression (LASSO) and recursive feature elimination for support vector machines (SVM-RFE) machine learning algorithms. The ferroptosis scores based on seven selected genes were constructed to evaluate the ferroptosis characteristics of ASD. Results: We identified 16 differentially expressed FRGs in ASD children compared with controls. Two distinct molecular clusters associated with ferroptosis were identified in ASD. Analysis of immune infiltration revealed immune heterogeneity between the two clusters. Cluster2, characterized by a higher immune score and a larger number of infiltrated immune cells, exhibited a stronger immune response and was markedly enriched in immune response-related signaling pathways. Additionally, the ferroptosis scores model was capable of predicting ASD subtypes and immunity. Higher levels of ferroptosis scores were associated with immune activation, as seen in Cluster2. Lower ferroptosis scores were accompanied by relative immune downregulation, as seen in Cluster1. Conclusion: Our study systematically elucidated the intricate correlation between ferroptosis and ASD and provided a promising ferroptosis score model to predict the molecular clusters and immune infiltration cell profiles of children with ASD.

Project description:BackgroundSignificant progress has been made in elucidating the genetic underpinnings of Autism Spectrum Disorder (ASD). However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals.MethodsWe used the macaque Genotype and Phenotype (mGAP) resource consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes.ResultsWe demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-associated genes exhibit significant constraint in macaques (p = 9.4 × 10- 27). Among macaques, many key ASD-implicated genes were observed to harbour predicted damaging mutations. A small number of key ASD-implicated genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D, MBD5, AUTS2 and NRXN1). Constraint was also observed across genes associated with intellectual disability (p = 1.1 × 10- 46), epilepsy (p = 2.1 × 10- 33) and schizophrenia (p = 4.2 × 10- 45), and for an overlapping neurodevelopmental gene set (p = 4.0 × 10- 10).LimitationsThe lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates.ConclusionThe presence of pathological mutations in ASD genes among macaques, along with evidence of similar genetic constraints to those in humans, provides a strong rationale for further investigation of genotype-phenotype relationships in macaques. This highlights the importance of developing primate models of ASD to elucidate the neurobiological underpinnings and advance approaches for precision medicine and therapeutic interventions.

Dataset Information

Functional and molecular characterization of a non-human primate model of autism spectrum disorder shows similarity with the human disease.

Publications

Functional and molecular characterization of a non-human primate model of autism spectrum disorder shows similarity with the human disease.

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