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.
Rett Syndrome is a debilitating neurodevelopmental disorder that affects 1 in 10,000 females annually with no definitive treatment to ameliorate symptoms. We propose to examine BDNF signaling effects on astrocyte morphological complexity, and how its loss contributes to aberrant astrocyte morphology in Rett Syndrome through a powerful combination of molecular, genetic, and imaging techniques. Given that astrocytes constitute nearly 60% of total human brain and spinal cord volume, understanding mechanisms contributing to their dysfunction is critical to understanding and treating Rett Syndrome.
