Molecular causes of cognitive and autistic disabilities

 描述(由申请人提供)：智力障碍(ID)和自闭症谱系障碍(ASD)非常普遍。10-30%的自闭症患者会发生癫痫发作，导致终身残疾。由于这些疾病在分子上定义不清，因此很大程度上缺乏治疗。对ASD和ID家族进行的大规模基因筛查已经确定了数百个风险基因。令人信服的证据表明，风险基因集中在神经元的几个关键生物学过程中。我们的资助集中在两个-β-连环蛋白(β-CAT)/典范Wnt途径和突触功能上。β-CAT在钙粘蛋白、突触黏附复合体和典型的Wnt信号转导中具有双重功能。这两条通路都调节突触的密度和可塑性，以及大脑中电路网络的形成和功能。我们认为，β-CAT水平及其相关途径的最佳范围是必不可少的；水平过高或 低水平会导致放松管制和大脑功能障碍。作为对这一假说的支持，几个与人类ID、ASD和癫痫相关的基因被预测会导致β-CAT/典型的Wnt途径功能的丧失或获得，强调了阐明大脑中β-CAT水平异常引起的变化的重要性。此外，我们最近的研究表明，在小鼠神经元中，腺瘤性息肉病结肠蛋白的靶向性缺失会导致认知和自闭症样残疾和癫痫发作。腺瘤性息肉病结肠蛋白是典型的Wnt途径中β-CAT水平的主要负调控因子。突触的数量、成熟和功能都发生了改变。分子改变包括β-CAT的过度表达以及与之相关的WNT靶基因表达和钙粘附素突触黏附复合体的变化。我们建议对大脑中异常的β-CAT水平的影响进行直接测试。目的1研究将使用我们的新的小鼠系，在神经元中有条件地过度表达β-CAT来模拟功能获得。目的2研究将使用我们的新的β-CAT有条件缺失的小鼠系来建立功能丧失的模型。我们将定义认知和行为表型，它们的严重性，以及高和低β-CAT引起的分子和功能变化。AIM3研究将确定纠正过量β-CAT水平的药物治疗，并测试对APC条件性基因敲除小鼠认知缺陷、孤独症样行为和癫痫发作的改善情况。我们还将测试分子和功能改变的整改情况。初步数据为我们计划的研究提供了强有力的支持。所有3个AIMS都将使用相同的多学科方法来定义由异常的β-CAT水平引起的行为、分子和功能变化。该项目将利用雅各布实验室在突触生物学方面的互补专业知识，以及杜拉实验室在电生理和网络分析方面的互补专业知识。我们的研究将从分子、突触和电路水平阐明β-CAT的改变如何在ID、ASD和癫痫发作的病理生理学中起作用。我们的发现还将为我们提供对 靶向β-CAT及其相关通路的治疗潜力，从而为这些神经发育障碍的未来治疗策略的设计提供信息。

 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.