Mechanisms underlying the Cerebellar Contribution to Autism in Mouse Models of Tuberous Sclerosis Complex

描述（由申请人提供）：自闭症是一种破坏性的神经发育障碍，其特征是社交障碍，限制性思维/重复行为和3岁之前出现的沟通障碍。由于对潜在的病理生理学缺乏了解，治疗开发受到阻碍。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。多发性硬化症是一种由Tsc 1或Tsc 2突变引起的遗传性疾病，自闭症的发病率很高（约50%）。TSC患者具有显著的小脑异常，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区分TSC患者与自闭症。为了研究小脑对自闭症行为的贡献，Tsai博士专门在小脑浦肯野细胞（PC）中产生了Tsc 1缺失的小鼠模型。PC中Tsc 1的缺失足以在小鼠中产生自闭症样行为，此外还导致神经元形态异常和电兴奋性受损。由于mTOR随着Tsc 1的丢失而升高，Tsai博士用mTOR特异性抑制剂雷帕霉素治疗了这个模型，从而预防了病理和行为异常。这些研究结果导致的假设，异常PC形态和功能有助于自闭症样表型，同时也提供了基础，描绘神经解剖学基础和关键时期的发展和治疗自闭症样行为。为了验证这些假设，目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Tsc 1突变小鼠中自闭症样行为的分子和神经解剖学机制。(2)定义浦肯野细胞特异性Tsc 1突变小鼠的自闭症样行为的关键期。(3)定义小脑神经解剖学基础的自闭症样行为。这些研究将提供重要的分子，行为和神经解剖学的见解小脑功能障碍的自闭症的病理生理学的贡献，同时也提供了合理的治疗这些毁灭性的疾病的发展的基础。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博士是理解TSC神经学基础的先驱，Wade Regehr博士是小脑电路和生理学方面的著名专家。神经病学系将提供一个肥沃的环境来定义小脑对自闭症的贡献。蔡博士是一位儿童神经学家， 在波士顿儿童医院他的职业目标是成为一名独立的医学科学家，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。这个指导奖将为蔡博士提供结构化，富有成效的培训经验，这将有助于他成为一名独立的医生科学家。

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.