Monika and Natalie’s project

Regulation of the choroid plexus physiology by ion channels and bioactive lipid signaling

We are currently studying steroid regulation of the ion channels and transporters expressed in the choroid plexus epithelial cells (CPEC). The choroid plexus (CP), located within each ventricle of the brain, is a secretory epithelial tissue, manufacturing 80% of the cerebrospinal fluid (CSF) in the brain¹. In each ventricle, the CP consists of a single layer of cuboidal epithelial cells lining a complex network of capillaries^1,2. These choroid plexus epithelial cells form tight junctions with one another, creating a blood-CSF barrier to prevent paracellular passage of molecules and thereby controlling the composition of CSF³. The CP receives more blood flow per gram of tissue than any other tissue in the body and produces 400-600mL CSF per 24 hours^2,4,5.  The CSF has three main functions: to protect the brain, supply nutrients to the central nervous system and remove waste products from cerebral metabolism. 

Cerebrospinal fluid formation begins as plasma is passed through a network of fenestrated capillaries in the basement membrane of the choroid plexus epithelial cells¹. A Na⁺/K⁺ ATPase in the apical membrane actively pumps out 3 Na⁺ out of the cell and 2 K⁺ into the cell, against both of their concentration gradient, with the use of one ATP molecule^1,3,6. Anion transport of Cl^– and HCO₃^– across the luminal membrane follows. The transcellular transport of Na⁺ and Cl^– ions generates an osmotic gradient that, in turn, drives the secretion of water from the plasma, across the choroid plexus epithelium, to the ventricular lumen through the aquaporin 1 (AQP1) channel¹. Lastly, the K⁺ ions that were brought into the cell by Na⁺/K⁺ ATPase are then pumped out by apical facing K⁺ channels. However, regulation of these channels and transporters is not fully understood.

References

1. Damkier, H. H., Brown, P. D. & Praetorius, J. Cerebrospinal fluid secretion by the choroid plexus. Physiological Reviews vol. 93 1847–1892 (2013).
2. Kaur, C., Rathnasamy, G. & Ling, E. A. The choroid plexus in healthy and diseased brain. J. Neuropathol. Exp. Neurol. 75, 198–213 (2016).
3. Spector, R., Keep, R. F., Robert Snodgrass, S., Smith, Q. R. & Johanson, C. E. A balanced view of choroid plexus structure and function: Focus on adult humans. Experimental Neurology vol. 267 78–86 (2015).
4. Karimy, J. K. et al. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat. Med. 23, 997–1003 (2017).
5. Kant, S., Stopa, E. G., Johanson, C. E., Baird, A. & Silverberg, G. D. Choroid plexus genes for CSF production and brain homeostasis are altered in Alzheimer’s disease. Fluids Barriers CNS 15, (2018).
6. Kaur, C., Rathnasamy, G. & Ling, E. A. The choroid plexus in healthy and diseased brain. Journal of Neuropathology and Experimental Neurology vol. 75 198–213 (2016).