Development and function of the meninges arachnoid barrier

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Project Summary The central nervous system (CNS) is protected by two barrier systems, the blood brain-barrier (BBB) and the blood-cerebrospinal fluid barrier (B-CSFB). These barrier systems have unique cellular properties that regulate the molecules and cells that can enter or exit the CNS and the CSF. CNS barriers are essential for development and health but breakdown in a variety of diseases, causing or exacerbating CNS pathology. A detailed under- standing of CNS barriers is also essential for efficient drug delivery to the brain and spinal cord. The development and function of the B-CSFB at the level of the meninges, a trilayered structure that surrounds the CNS, is poorly understood. This is despite evidence implicating meninges-located barriers in perinatal and adult diseases as an early site of immune cell activation and entry in neuroinflammation. One of two barrier structures in the me- ninges is the arachnoid barrier layer, which segregates the outer meningeal dura and its non-barrier vasculature, from the CSF and cell types in the subarachnoid space. Unlike the BBB and other parts of the B-CSFB, nothing is known about mechanisms of arachnoid barrier cell specification, timing of layer maturation or acquisition of functional properties. Further, only a few studies have looked at arachnoid barrier dysfunction in CNS diseases and so far, no studies have tested if an immature arachnoid barrier has enhanced vulnerability to breakdown. We have combined our knowledge of CNS vascular and BBB development with our unique expertise in the meninges to develop new tools to study the arachnoid barrier. Experiments proposed here build upon our initial discoveries to identify mechanisms that underlie arachnoid barrier layer development, investigate arachnoid bar- rier maturation and function, and measure its response in insult. To do this we will: 1) utilize in vivo and culture models to uncover the molecular mechanisms of arachnoid barrier cell specification, 2) use our new model where we perturb arachnoid barrier formation prenatally to determine its role in establishing separate meninges immune cell and vascular compartments and in protecting the fetal brain in an animal model of maternal infection 3) identify the cellular and molecular mechanisms of arachnoid barrier breakdown in bacterial meningitis. Comple- tion of this work will substantially advance the field of CNS barrier systems. It will provide the first model of arachnoid barrier development including the cellular and molecular mechanisms and the timing of emergence of barrier properties. It will provide important information about the function of the arachnoid barrier. Experiments proposed here focus on the prenatal brain however findings will set the stage for future studies in postnatal and adult function. Third, it will provide the most detailed analysis to date of arachnoid barrier response to CNS insult, paving the way for future studies in other CNS diseases. In the long term, this new knowledge has the potential to be used to design new ways to limit crossing of molecules and cells at the arachnoid barrier to treat disease or increase crossing of drug therapeutics to access the CNS.