Mechanisms Underlying the Cerebellar Contribution to Autism in Mouse Models of Tu

Tu 小鼠模型中小脑对自闭症的贡献机制

• 批准号: 8566760
• 负责人: Peter T. Tsai
• 金额: $ 19.05万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566760
• 关键词: Age; Autistic Disorder; Award; Axon; Behavior; Behavior Disorders; Behavioral; Biological; Biological Models; Boston; Cellular Morphology; Cerebellar Diseases; Cerebellum; Child; Clinic; Commit; Communication impairment; Dendritic Spines; Designer Drugs; Development; Disease; Early treatment; Environment; Eph Family Receptors; Foundations; Functional Imaging; Functional disorder; Future; Generations; Genes; Goals; Healthcare; Hereditary Disease; Impairment; Individual; Laboratories; Lead; Learning Disorders; Lesion; Maps; Mentors; Mentorship; Modality; Modeling; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; Neuroanatomy; Neurodevelopmental Disorder; Neurologic; Neurologist; Neurology; Neurons; Pathogenesis; Pathology; Patients; Pediatric Hospitals; Phenotype; Phosphotransferases; Physicians; Physiology; Population; Prevalence; Prevention; Publishing; Purkinje Cells; Role; Scientist; Sirolimus; Structure; Synapses; TSC1/2 gene; Testing; Therapeutic; Thinking; Time; Training; Transgenic Mice; Treatment Efficacy; Tuberous Sclerosis; Tuberous sclerosis protein complex; United States; Withdrawing Treatments; Work; autistic behaviour; base; career; critical period; defined contribution; experience; human FRAP1 protein; improved; inhibitor/antagonist; insight; life time cost; mouse model; mutant; neuronal circuitry; neuronal excitability; postnatal; prevent; public health relevance; receptor; research study; restrictive repetitive behavior; social; therapeutic development; therapeutic target; therapy development; vocalization

DESCRIPTION (provided by applicant): Autism is a devastating neurodevelopmental disorder characterized by social impairment, restrictive thinking/repetitive behaviors, and communication impairment presenting before age three. Therapeutic development has been hampered by poor understanding of the underlying pathophysiology. Cerebellar dysfunction has been implicated in autism pathogenesis; however, the precise role for the cerebellum in these disorders remains unclear. Tuberous Sclerosis Complex, a genetic disorder caused by mutation in either Tsc1 or Tsc2, has high rates of autism (~50%). Patients with TSC have significant cerebellar abnormalities, which correlate with the presence of autism in TSC, while functional imaging with cerebellar dysfunction also differentiates TSC patients with autism. To investigate the cerebellar contribution to autistic behaviors, Dr. Tsai generated a mouse model with Tsc1 loss specifically in cerebellar Purkinje cells (PCs). Loss of Tsc1 in PCs was sufficient to generate autistic-like behaviors in mice in addition to abnormal neuronal morphology and impaired electric excitability. As mTOR is elevated with loss of Tsc1, Dr. Tsai treated this model with the mTOR specific inhibitor, rapamycin, which resulted in the prevention of pathological and behavioral abnormalities. These findings lead to the hypothesis that abnormal PC morphology and function contribute to autistic-like phenotypes while also providing the foundation to delineate the neuroanatomical basis and critical periods for development and treatment of autistic-like behaviors. To test these hypotheses, the current mentored training proposal has the following specific aims (1) Determine the molecular and neuroanatomical mechanisms underlying autistic-like behaviors in Purkinje cell-specific Tsc1 mutant mice. (2) Define the critical periods for autistic-like behaviors in Purkinje cell specific Tsc1 mutant mice. (3) Define the cerebellar neuroanatomical underlying autistic-like behaviors. These studies will provide important molecular, behavioral, and neuroanatomical insight into the contribution of cerebellar dysfunction to the pathophysiology of autism while also providing the foundation for rational therapeutic development for these devastating disorders. These studies will be performed under the dual mentorship of Dr. Mustafa Sahin, a pioneer in the understanding of the neurological basis for TSC, and Dr. Wade Regehr, a renowned expert in cerebellar circuitry and physiology. The Department of Neurology will provide a fertile environment to define the cerebellar contribution to autism. Dr. Tsai is a child neurologist who directs the Cerebellar Disorders Clinic at Boston Children's Hospital. His career goal is to become an independent physician-scientist committed to understanding the contribution of cerebellar dysfunction to behavioral, learning, and neurodevelopmental disorders such as autism. This mentored award will provide Dr. Tsai a structured, productive training experience that will bolster his transition to becoming an independent physician-scientist.

描述（由申请人提供）：自闭症是一种破坏性的神经发育障碍，其特征是三岁前出现的社交障碍、限制性思维/重复行为和沟通障碍。由于对潜在的病理生理学了解不足，治疗的发展受到阻碍。小脑功能障碍与自闭症发病机制有关。然而，小脑在这些疾病中的确切作用仍不清楚。结节性硬化症是一种由 Tsc1 或 Tsc2 突变引起的遗传性疾病，自闭症发病率很高（约 50%）。 TSC 患者有明显的小脑异常，这与 TSC 中自闭症的存在相关，而小脑功能障碍的功能成像也可区分 TSC 患者与自闭症。为了研究小脑对自闭症行为的影响，蔡博士建立了一个 Tsc1 缺失的小鼠模型，特别是在小脑浦肯野细胞 (PC) 中。除了神经元形态异常和电兴奋性受损之外，PC 中 Tsc1 的缺失足以在小鼠中产生类似自闭症的行为。由于 mTOR 随着 Tsc1 的缺失而升高，蔡博士用 mTOR 特异性抑制剂雷帕霉素治疗该模型，从而预防了病理和行为异常。这些发现提出了这样的假设：异常的 PC 形态和功能会导致类似自闭症的表型，同时也为描述神经解剖学基础以及类似自闭症行为的发展和治疗的关键时期提供了基础。为了测试这些假设，当前的指导培训计划有以下具体目标（1）确定浦肯野细胞特异性 Tsc1 突变小鼠自闭症样行为背后的分子和神经解剖学机制。 (2) 定义浦肯野细胞特异性 Tsc1 突变小鼠的自闭症样行为的关键期。 (3) 定义自闭症样行为背后的小脑神经解剖学。这些研究将为小脑功能障碍对自闭症病理生理学的影响提供重要的分子、行为和神经解剖学见解，同时也为这些破坏性疾病的合理治疗发展提供基础。这些研究将在了解 TSC 神经学基础的先驱 Mustafa Sahin 博士和小脑回路和生理学著名专家 Wade Regehr 博士的双重指导下进行。神经内科将提供一个丰富的环境来定义小脑对自闭症的影响。蔡医生是一名儿童神经科医生，负责小脑疾病诊所的指导 在波士顿儿童医院。他的职业目标是成为一名独立的医师科学家，致力于了解小脑功能障碍对行为、学习和神经发育障碍（如自闭症）的影响。这个指导奖项将为蔡博士提供结构化、富有成效的培训经验，这将有助于他向独立医师科学家的过渡。