The production of CSF depends on the transcellular movement of Na + primarily driven by the Na +/K +-ATPase expressed at the luminal membrane facing the CSF. This enables the passage of compounds from the blood to the epithelial cells. The epithelial cells are connected by tight junctions making the epithelial layer relatively tight, whereas the underlying fenestrated capillaries are relatively leaky. The plexi consist of a single layer of epithelial cells residing on a basement membrane, connective tissue, and fenestrated capillaries ( Figure 1A). The choroid plexi develop from the ependyma protruding from the pia mater into the lateral, third, and fourth ventricles ( Damkier et al., 2013 Hladky and Barrand, 2014). The classic theory states that the choroid plexi are the primary sources of CSF production. Several theories have been proposed to explain how CSF is produced. The fluid is a mixture of water, proteins at low concentrations, ions, neurotransmitters, and glucose that is renewed three to four times per day ( Damkier et al., 2013 Hladky and Barrand, 2014 Spector et al., 2015). The CSF is a clear, colorless fluid that occupies the ventricular system, the cerebral and spinal subarachnoid spaces, and the perivascular spaces in the CNS. This will provide the basis for highlighting the knowledge gaps that should be addressed through further research. This review aims to describe the theories underlying the CSF system in relation to neurological diseases in the brain and spinal cord. Of utmost importance is bridging the knowledge gap between the brain and the spinal cord regarding the controversies of a glymphatic system and a lymphatic network, and further to understanding how these complex relationships in the CSF system contribute to health and disease. Yet, some aspects of the CSF system remain to be fully clarified, notably along the spinal cord. The CSF system constitutes a crucial role in the CNS as it provides mechanical protection, ensures homeostasis, and facilitates communication between the CNS and peripheral nervous system, lymphatic system, vascular system, and immune system ( Damkier et al., 2013 Aspelund et al., 2015 Louveau et al., 2015 Adigun and Al-Dhahir, 2021). Renewed attention has come to the cerebrospinal fluid (CSF) system due to its importance for central nervous system (CNS) homeostasis. This review briefly summarizes the CSF system and its implications for CNS diseases and highlights the knowledge gaps that require further research. Yet, several aspects remain to be fully clarified, notably along the spinal cord as the preponderance of research has focused on the brain. In recent years, extensive research has resulted in vastly improved understanding of the CSF system in health and disease.

The system of CSF refers to all components involved in CSF production, movement, and absorption. 3Comparative Medicine Lab, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, DenmarkĪ comprehensive understanding of the cerebrospinal fluid (CSF) system is essential for our understanding of health and disease within the central nervous system (CNS).

2Department of Biomedicine, Faculty of Health, Aarhus University, Aarhus, Denmark.

1Department of Neurosurgery, Aarhus University Hospital, Aarhus, Denmark.

Thea Overgaard Wichmann 1*, Helle Hasager Damkier 2 and Michael Pedersen 3

Brain fluid