Molecular causes of cognitive and autistic disabilities

认知障碍和自闭症障碍的分子原因

• 批准号: 9326368
• 负责人: Michele H. Jacob
• 金额: $ 46.89万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326368
• 关键词: Adenomatous Polyposis Coli Protein; Adhesions; Affect; Age; Autistic Disorder; Behavior; Behavioral; Biochemical; Biological Process; Biology; Brain; Brain region; CTNNB1 gene; Cadherins; Child; Cognitive; Cognitive deficits; Collaborations; Complex; Corpus striatum structure; Data; Development; Diagnosis; Disease; Electroencephalography; Electrophysiology (science); Exhibits; Family; Felis catus; Functional disorder; Future; Gene Expression; Gene Mutation; Gene Targeting; General Population; Genes; Genetic; Genetic Screening; Glutamates; Grant; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Inherited; Intellectual functioning disability; Knockout Mice; Lead; Link; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Pathway Analysis; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prefrontal Cortex; Regulation; Scaffolding Protein; Seizures; Severities; Short-Term Memory; Signal Transduction; Slice; Synapses; Tankyrase; Techniques; Testing; Therapeutic; Treatment Efficacy; WNT Signaling Pathway; autism spectrum disorder; beta catenin; brain dysfunction; density; design; disability; effective intervention; experimental study; gain of function; improved; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; loss of function; loss of function mutation; mouse model; mutant mouse model; neural circuit; novel; overexpression; proband; protein B; public health relevance; risk variant; synaptic function; targeted treatment

 DESCRIPTION (provided by applicant): Intellectual disabilities (ID) and autism spectrum disorders (ASD) are highly prevalent. Seizures occur in 10- 30% of individuals with ASD, leading to lifelong disabilities. Treatments are largely lacking because these disorders are molecularly ill-defined. Large-scale genetic screens of families with ASD and ID have identified hundreds of risk genes. Compelling evidence suggests that the risk genes converge on a few key biological processes in neurons. Our grant focuses on two- the β-catenin (β-cat)/ canonical Wnt pathway and synaptic function. β-cat has dual functions in cadherin synaptic adhesion complexes and canonical Wnt signal transduction. Both pathways modulate synapse density and plasticity, as well as the formation and function of circuit networks in the brain. We propose that an optimal range of β-cat levels and its associated pathways is essential; levels too high or low lead to deregulation and brain dysfunction. As support for this hypothesis, several human ID, ASD, and seizure linked genes are predicted to cause either loss- or gain-of-function of the β-cat/ canonical Wnt pathway, highlighting the importance of elucidating the changes caused by aberrant β-cat levels in the brain. Further, our recent studies show that targeted deletion in mouse neurons of adenomatous polyposis coli protein (APC), a major negative regulator of β-cat levels in the canonical Wnt pathway, leads to cognitive and autistic-like disabilities and seizures. Synapse number, maturation and function are altered. Molecular alterations include excessive β-cat and associated changes in Wnt target gene expression and cadherin synaptic adhesion complexes. We propose direct tests of the effects of aberrant β-cat levels in the brain. Aim 1 studies will use our new mouse line with β-cat conditional overexpression in neurons to model gain-of-function. Aim 2 studies will use our new mouse line with conditional deletion of β-cat to model loss-of- function. We will define the cognitive and behavioral phenotypes, their severity, and the molecular and functional changes caused by high versus low β-cat. Aim3 studies will identify drug treatments that correct excessive β-cat levels and test for amelioratio of cognitive deficits, autism-like behaviors and seizures in APC conditional knockout mice. We will also test for rectification of the molecular and functional alterations. Preliminary data provde strong support for our planned studies. All 3 Aims will use the same multidisciplinary approaches to define the behavioral, molecular and functional changes induced by aberrant β-cat levels. This project will utilize the complementary expertise of the Jacob lab in synaptic biology and new genetic mouse models of cognitive and autism-like disabilities, with co-morbid seizures, and the Dulla lab in electrophysiological and network analysis. Our studies will elucidate how alterations in β-cat contribute to the pathophysiology of ID, ASD and seizures on a molecular, synaptic, and circuit level. Our findings will also provide critical insights into the therapeutic potential of targeting β-cat and its associated pathways and thereby inform the design of future therapeutic strategies for these neurodevelopmental disorders.

 DESCRIPTION (provided by applicant): Intellectual disabilities (ID) and autism spectrum disorders (ASD) are highly prevalent. Seizures occur in 10- 30% of individuals with ASD, leading to lifelong disabilities. Treatments are largely lacking because these disorders are molecularly ill-defined. Large-scale genetic screens of families with ASD and ID have identified hundreds of risk genes. Compelling evidence suggests that the risk genes converge on a few key biological processes in neurons. Our grant focuses on two- the β-catenin (β-cat)/ canonical Wnt pathway and synaptic function. β-cat has dual functions in cadherin synaptic adhesion complexes and canonical Wnt signal transduction. Both pathways modulate synapse density and plasticity, as well as the formation and function of circuit networks in the brain. We propose that an optimal range of β-cat levels and its associated pathways is essential; levels too high or low lead to deregulation and brain dysfunction. As support for this hypothesis, several human ID, ASD, and seizure linked genes are predicted to cause either loss- or gain-of-function of the β-cat/ canonical Wnt pathway, highlighting the importance of elucidating the changes caused by aberrant β-cat levels in the brain. Further, our recent studies show that targeted deletion in mouse neurons of adenomatous polyposis coli protein (APC), a major negative regulator of β-cat levels in the canonical Wnt pathway, leads to cognitive and autistic-like disabilities and seizures. Synapse number, maturation and function are altered. Molecular alterations include excessive β-cat and associated changes in Wnt target gene expression and cadherin synaptic adhesion complexes. We propose direct tests of the effects of aberrant β-cat levels in the brain. Aim 1 studies will use our new mouse line with β-cat conditional overexpression in neurons to model gain-of-function. Aim 2 studies will use our new mouse line with conditional deletion of β-cat to model loss-of- function. We will define the cognitive and behavioral phenotypes, their severity, and the molecular and functional changes caused by high versus low β-cat. Aim3 studies will identify drug treatments that correct excessive β-cat levels and test for amelioratio of cognitive deficits, autism-like behaviors and seizures in APC conditional knockout mice. We will also test for rectification of the molecular and functional alterations. Preliminary data provde strong support for our planned studies. All 3 Aims will use the same multidisciplinary approaches to define the behavioral, molecular and functional changes induced by aberrant β-cat levels. This project will utilize the complementary expertise of the Jacob lab in synaptic biology and new genetic mouse models of cognitive and autism-like disabilities, with co-morbid seizures, and the Dulla lab in electrophysiological and network analysis. Our studies will elucidate how alterations in β-cat contribute to the pathophysiology of ID, ASD and seizures on a molecular, synaptic, and circuit level. Our findings will also provide critical insights into the therapeutic potential of targeting β-cat and its associated pathways and thereby inform the design of future therapeutic strategies for these neurodevelopmental disorders.