{"title":"Neurodevelopmental impact of CNV models in ASD: Recent advances and future directions","authors":"Kota Tamada, Toru Takumi","doi":"10.1016/j.conb.2025.103001","DOIUrl":null,"url":null,"abstract":"<div><div>Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and restricted, repetitive behaviors. ASD exhibits a strong genetic basis, with rare and common genetic variants contributing to its etiology. Copy number variations (CNVs), deletions or duplications of chromosomal segments, have emerged as key contributors to ASD risk. Rare CNVs often demonstrate large effect sizes and can directly cause ASD, while common variants collectively exert subtle influences. Recent advances have identified numerous ASD-associated CNVs, including recurrent loci such as 1q21.1, 2p16.3, 7q11.23, 15q11.2, 15q11-q13, 16p11.2 and 22q11.2. Mouse models carrying these CNVs have provided profound insights into the underlying neurobiological mechanisms. Recent studies integrating transcriptomic, proteomic, and functional imaging approaches have revealed alterations in synaptic function, neuronal differentiation, myelination, metabolic pathways, and circuit connectivity. Notably, investigations leveraging conditional knockout models, high magnetic field MRI, and single-cell analyses highlight disruptions in excitatory-inhibitory balance, white matter integrity, and dynamic gene regulatory networks. Parallel human-based approaches, including iPSC-derived neurons, cerebral organoids, and large-scale single-nucleus sequencing, are combined with animal model data. These integrative strategies promise to refine our understanding of ASD's genetic architecture, bridging the gap between fundamental discoveries in model organisms and clinically relevant biomarkers, subtypes, and therapeutic targets in humans. This review summarizes key findings from recent CNV mouse model studies and highlights emerging technologies applied to human ASD samples. Finally, we outline prospects for translating findings from mouse studies to humans. By illuminating both unique and convergent genetic mechanisms, these advances offer a critical framework for unraveling etiological complexity in ASD.</div></div>","PeriodicalId":10999,"journal":{"name":"Current Opinion in Neurobiology","volume":"92 ","pages":"Article 103001"},"PeriodicalIF":4.8000,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Opinion in Neurobiology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0959438825000327","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and restricted, repetitive behaviors. ASD exhibits a strong genetic basis, with rare and common genetic variants contributing to its etiology. Copy number variations (CNVs), deletions or duplications of chromosomal segments, have emerged as key contributors to ASD risk. Rare CNVs often demonstrate large effect sizes and can directly cause ASD, while common variants collectively exert subtle influences. Recent advances have identified numerous ASD-associated CNVs, including recurrent loci such as 1q21.1, 2p16.3, 7q11.23, 15q11.2, 15q11-q13, 16p11.2 and 22q11.2. Mouse models carrying these CNVs have provided profound insights into the underlying neurobiological mechanisms. Recent studies integrating transcriptomic, proteomic, and functional imaging approaches have revealed alterations in synaptic function, neuronal differentiation, myelination, metabolic pathways, and circuit connectivity. Notably, investigations leveraging conditional knockout models, high magnetic field MRI, and single-cell analyses highlight disruptions in excitatory-inhibitory balance, white matter integrity, and dynamic gene regulatory networks. Parallel human-based approaches, including iPSC-derived neurons, cerebral organoids, and large-scale single-nucleus sequencing, are combined with animal model data. These integrative strategies promise to refine our understanding of ASD's genetic architecture, bridging the gap between fundamental discoveries in model organisms and clinically relevant biomarkers, subtypes, and therapeutic targets in humans. This review summarizes key findings from recent CNV mouse model studies and highlights emerging technologies applied to human ASD samples. Finally, we outline prospects for translating findings from mouse studies to humans. By illuminating both unique and convergent genetic mechanisms, these advances offer a critical framework for unraveling etiological complexity in ASD.
期刊介绍:
Current Opinion in Neurobiology publishes short annotated reviews by leading experts on recent developments in the field of neurobiology. These experts write short reviews describing recent discoveries in this field (in the past 2-5 years), as well as highlighting select individual papers of particular significance.
The journal is thus an important resource allowing researchers and educators to quickly gain an overview and rich understanding of complex and current issues in the field of Neurobiology. The journal takes a unique and valuable approach in focusing each special issue around a topic of scientific and/or societal interest, and then bringing together leading international experts studying that topic, embracing diverse methodologies and perspectives.
Journal Content: The journal consists of 6 issues per year, covering 8 recurring topics every other year in the following categories:
-Neurobiology of Disease-
Neurobiology of Behavior-
Cellular Neuroscience-
Systems Neuroscience-
Developmental Neuroscience-
Neurobiology of Learning and Plasticity-
Molecular Neuroscience-
Computational Neuroscience