Astrocytes are a primary target of neuronal-derived BDNF: a novel mechanism for dysfunction in Rett Syndrome

项目摘要/摘要 成熟的星形胶质细胞可以说是中枢神经系统中形态最复杂的细胞。这 复杂性与这种细胞类型的几个最有特点的功能有关，包括 神经递质再摄取、K+稳态和血脑屏障的维持。虽然我们知道 发育时间窗当星形胶质细胞形态成熟和细化时，我们所知甚少 关于这一过程的其他信息。脑源性神经营养因子(BDNF)是一种重要的生长因子，主要由 神经元，参与神经元的发育和成熟，包括神经元的生长和突触 精致。我们为这笔赠款产生的初步数据表明，星形胶质细胞表达高水平 脑源性神经营养因子受体TrkB与神经元相比。特别是，TrkB的截断版本TrkB.T1是 优势受体表达。TrkB.T1在星形胶质细胞中表达最高 星形胶质细胞的形态细化和成熟，这也是一个发育的时间窗口 符合神经元BDNF的最高表达水平。脑源性神经营养因子表达缺失是 神经发育障碍Rett综合征，最近的出版物表明星形胶质细胞有一个 显著降低了形态的复杂性，在这种疾病中是功能失调的。这些发现导致了 BDNF/TrkB.T1信号是星形胶质细胞形态的重要调节因子的假设 成熟和神经元BDNF表达减少通过调节星形胶质细胞功能障碍 Rett综合征的星形胶质细胞形态。我们建议检测BDNF对星形胶质细胞形态的影响 利用体外和体内分子、遗传和成像技术的组合。此外，我们还将 检测脑源性神经营养因子/TrkB.T1信号降低是否与Rett综合征的星形胶质细胞形态异常有关 这可能有助于阐明星形胶质细胞功能障碍是如何导致这种毁灭性的 疾病。

Project Summary/Abstract Mature astrocytes are arguably the most morphologically complex cells in the central nervous system. This complexity is associated with several of the most well characterized functions of this cell type, including neurotransmitter reuptake, K+ homeostasis, and blood-brain barrier maintenance. While we know the developmental time window when astrocyte morphological maturation and refinement occurs, we know little else about this process. Brain derived neurotrophic factor (BDNF) is a critical growth factor secreted largely by neurons and involved in the development and maturation of neurons, including neuronal growth and synapse refinement. Preliminary data we have generated for this grant demonstrates that astrocytes express high levels of the BDNF receptor TrkB when compared to neurons. In particular, the truncated version of TrkB, TrkB.T1 is the predominate receptor expressed. TrkB.T1 expression is highest in astrocytes during the critical period of astrocyte morphological refinement and maturation, a developmental time window which also happens to coincide with highest neuronal BDNF expression levels. Loss of BDNF expression is a hallmark of neurodevelopment disorder Rett Syndrome, and recent publications indicate that astrocytes have a significantly reduced morphological complexity and are dysfunctional in this disease. These findings have led us to the hypothesis that BDNF/TrkB.T1 signaling is an important mediator of astrocyte morphological maturation and that reduced neuronal BDNF expression contributes to astrocyte dysfunction by modulating astrocyte morphology in Rett Syndrome. We propose to examine BDNF’s influence on astrocyte morphology utilizing a combination of in vitro and in vivo molecular, genetic, and imaging techniques. Additionally, we will examine if reduced BDNF/TrkB.T1 signaling contribute to aberrant astrocyte morphology in Rett syndrome which may shed light on how astrocyte dysfunction contributes to the pathophysiology of this devastating disease.