Elucidating structures and functions in the arachnoid barrier

Less is known about the structural and functional importance of the arachnoid barrier than any other CNS barrier, including the blood-brain barrier. Animal models of arachnoid barrier impairment are not known/have not been analyzed. The sophisticated architecture and cellular specialization of the arachnoid barrier includes tight- and tricellular junctions joining two cell layers, direct contact with other arachnoid cells, and the specific expression of a broad repertoire of influx and efflux transporters, suggest major importance. Lack of understanding of the arachnoid barrier represents a conspicuous knowledge void in neurobiology. The Arrachnobarrier2.0 project seeks to elucidate and understand these features and to examine their pathophysiological importance. We will test the hypothesis that arachnoid barrier disruption may have serious consequences for CNS function. We will also test the hypothesis that the arachnoid barrier is responsive to diverse disease conditions and can contribute to disease pathophysiology. We hypothesize that the arachnoid barrier has regional cellular and molecular adaptations that underlie CSF transit from the subarachnoid space to dural lymphatics. Some of these sites are known, such as olfactory nerve and cranial nerve exit sites, whereas others are more speculative, such as arachnoid granulations and sites of bridging vein crossing. The three Specific Aims in this proposal will address these aspects of arachnoid barrier structure, function, molecular and regional heterogeneity, and pathophysiology. This proposal is innovative and has potential for ground-breaking discovery because arachnoid structure and function has remained elusive since its anatomic description ≈500 years ago and the discovery of its barrier properties ≈50 years ago. The project offers unique insights into the cellular and molecular composition of the arachnoid, its physiological function, regenerative capacity and pathophysiological roles.