Region-restricted astrocytes in neural circuit formation and function

描述（由申请人提供）：星形胶质细胞（AS）是中枢神经系统中数量最多的细胞，在神经发育和神经退行性疾病（包括自闭症相关疾病Rett综合征和脆性X综合征，肌萎缩性侧索硬化症（ALS）和亨廷顿氏病）的病理中越来越被认为是关键角色。本研究计划的目标是确定AS在指导功能性神经回路形成中的作用。K08指导临床科学家的申请人

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.