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

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缺乏了解，治疗的发展一直受到阻碍。小脑功能障碍与自闭症的发病机制有关；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基因突变引起的遗传性疾病，自闭症的发生率很高(~50%)。TSC患者有明显的小脑异常，这与TSC中自闭症的存在有关，而功能成像结合小脑功能障碍也可将TSC与自闭症相鉴别。为了研究小脑在自闭症行为中的作用，蔡博士建立了一个TSC1缺失的小鼠模型，该模型特定地位于小脑浦肯野细胞(PC)中。除了异常的神经元形态和受损的电兴奋性外，PC中TSC1的丢失足以产生小鼠的自闭症样行为。随着mTOR的升高和TSC1的缺失，蔡博士用mTOR的特异性抑制剂雷帕霉素治疗了这一模型，从而防止了病理和行为异常。这些发现导致了PC形态和功能异常导致孤独症样表型的假说，同时也为描绘孤独症样行为发生和治疗的神经解剖学基础和关键期提供了基础。为了验证这些假设，目前的指导培训方案有以下具体目标：(1)确定浦肯野细胞特异性TSC1突变小鼠自闭症样行为的分子和神经解剖学机制。(2)确定浦肯野细胞特异性TSC1突变小鼠的自闭症样行为的临界期。(3)明确自闭症样行为的小脑神经解剖学基础。这些研究将为小脑功能障碍在自闭症病理生理学中的作用提供重要的分子、行为和神经解剖学方面的见解，同时也为这些破坏性疾病的合理治疗开发提供基础。这些研究将在Mustafa Sahin博士和Wade Regehr博士的双重指导下进行，Mustafa Sahin博士是了解TSC神经学基础的先驱，Wade Regehr博士是小脑回路和生理学方面的著名专家。神经内科将提供一个肥沃的环境来确定小脑对自闭症的贡献。蔡医生是儿童神经科医生，是小脑疾病诊所的负责人 在波士顿儿童医院。他的职业目标是成为一名独立的内科科学家，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)的贡献。这个有指导的奖项将为蔡崇信博士提供一种有条理的、富有成效的培训经验，这将有助于他向独立内科科学家的转变。

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.