Region-restricted astrocytes in neural circuit formation and function

描述(申请人提供)：星形胶质细胞(AS)是中枢神经系统中数量最多的细胞，越来越多地被认为是神经发育和神经退行性疾病的关键参与者，包括自闭症相关疾病Rett综合征和脆性X综合征、肌萎缩侧索硬化症(ALS)和亨廷顿病。这项研究的目标是明确AS在引导功能神经回路形成中的作用。K08指导临床科学家的申请者 研究职业发展奖是精神病学系的精神病学家和临床讲师，也是加州大学旧金山分校大卫·罗维奇博士的博士后研究员。该提案概述了一项为期4年的职业发展计划和研究战略，其中包括Rowitch博士、John Rubenstein博士和Erik Ullian博士的指导，以实现下文所述的研究目标。总之，这些将使申请者能够实现一个职业目标，即经营一个独立的实验室，跨越神经胶质生物学和神经精神疾病的接口。形成这一建议基础的初步数据表明，引导分子Sema3a和EPHA5仅在腹侧脊髓AS中表达，而不是在背侧脊髓AS中表达。AS编码的Sema3a由腹侧AS分泌，对运动神经元的位置、出生后存活和突触发生具有局部影响，首次证明了分子上的异质性。该研究策略将这些发现扩展到机械和功能方向，以确定这些异质AS如何调节感觉运动回路的形成。目的研究编码的Sema3a蛋白极化运动神经元的机制及其对运动神经元树突生长的影响。目的二通过增加脑片电生理学训练，研究编码的Sema3a对运动神经元回路功能的影响。目的三通过AS编码的位置分子EPHA5的作用，确定AS在引导传入感觉神经元与运动神经元突触中的作用。综上所述，这些目标将极大地扩大我们对AS在确定的单突触中枢神经系统回路成熟过程中的作用的理解。拟议的培训和指导将使候选人为一个独立的研究职位做好准备，该职位负责AS在整个CNS神经回路形成中的作用。最终，这一战略和培训计划将为神经精神疾病的神经胶质治疗开辟新的研究途径。

DESCRIPTION (provided by applicant): Astrocytes (AS) are the most numerous cells in the central nervous system and are increasingly recognized as key players in the pathology of neurodevelopmental and neurodegenerative diseases including the autism- associated disorders Rett Syndrome and Fragile X syndrome, Amyotrophic Lateral Sclerosis (ALS), and Huntington's Disease. The goal of this research program is to define the role of AS in guiding the formation of functional neural circuits. The applicant for this K08 Mentored Clinical Scientist Research Career Development Award is a Psychiatrist and Clinical Instructor in the Department of Psychiatry, and a postdoctoral fellow with Dr. David Rowitch at the University of California San Francisco. This proposal outlines a 4-year career development plan and research strategy that includes mentorship by Dr. Rowitch, Dr. John Rubenstein and Dr. Erik Ullian to accomplish the research aims described below. Together, these will enable the applicant to fulfill a career goal of running an independent laboratory spanning the interface of glial biology and neuropsychiatric disease. Preliminary data that forms the basis for this proposal demonstrates that the guidance molecules Sema3a and EphA5 are uniquely expressed by ventral, but not dorsal spinal cord AS. AS-encoded Sema3a secreted from ventral AS has local effects on motor neuron position, postnatal survival, and synaptogenesis, demonstrating molecularly defined AS heterogeneity for the first time. The research strategy expands these findings in mechanistic and functional directions to determine how these heterogeneous AS modulate the formation of a sensorimotor circuit. Aim one will investigate the mechanism by which AS-encoded Sema3a protein polarizes motor neurons and its effects on motor neuron dendrite outgrowth. Aim two will study the effects of AS- encoded Sema3a in motor neuron circuit function, via additional training in slice electrophysiology. Aim three will determine the role of AS in guiding incoming sensory afferents that synapse on motor neurons through function of AS-encoded positional molecule EphA5. Together, these aims will greatly expand our understanding of the role of AS on the maturation of a defined monosynaptic CNS circuit. The training and mentorship proposed will prepare the candidate for an independent investigator position addressing the role of AS in neural circuit formation throughout the CNS. Ultimately, this strategy and training plan will open new avenues of research on glial-based treatments for neuropsychiatric disorders.