Mechanism Underlying Cerebrospinal Fluid Formation Identified

An ion transporter mechanism contributes to the transport of water from the blood into the brain, a new study on mice conducted at the University of Copenhagen reports. If the mechanism could be targeted with medicine, it may prove relevant for treating disorders involving increased intracranial pressure, including brain edema in connection with stroke, and hydrocephalus.

The brain is cushioned by intracranial fluid, which among other things, protects it from concussions. Every day, around a half-litre of water is transported from the blood to the brain through a thin tissue called choroid plexus. But exactly how this occurs has been a mystery.

Now, researchers at the University of Copenhagen have demonstrated, for the first time via mice, that the transport is not controlled by osmosis, as many used to believe. Instead, water is primarily transported to the brain via a so-called co-transporter that moves a certain amount of water when ions are transported across the choroid plexus tissue.

“This is new knowledge on a very important physiological process involving the most complex organ in the human body, the brain. If we are able to target this ion and water transporter with medicine, it would affect a number of disorders involving increased intracranial pressure, including brain haemorrhage, blood clots in the brain and hydrocephalus,”

neuroscientist Associate Professor Nanna MacAulay said.

Choroid Plexus

The researchers examined the choroid plexus in mice and tested whether water can be moved through the tissue even though the conditions required for osmotic water transport are missing. This turned out to be the case; a different process thus had to be responsible for water transport.

The choroid plexus is a branching network of cells that produces the cerebrospinal fluid in the ventricles of the brain. The choroid plexus consists of modified ependymal cells.

NKCC1 is located at the luminal membrane facing the ventricles.

NKCC1 is located at the luminal membrane facing the ventricles.
Credit: Annette B. Steffensen et al, CC-BY

They then did tests on live mice to see how fast brain fluid is produced when possible water transporters are inhibited. This revealed that the co-transporter in question is responsible for half of all fluid production for the brain cavity and is thus the main water transporter in this tissue.

“Of course, it would be groundbreaking ito use this mechanism as a target for medical treatment and turn down the inflow of water to the brain to reduce intracranial pressure. There are no effective medical treatments for a lot of disorders involving increased intracranial pressure. And at worst, the patient may suffer permanent damage and even die as a result of increased pressure. Therefore, this basic mechanism is an important find,”

said Nanna MacAulay.

The researchers stress that the structure of the responsible proteins is the same in mice as in the human cell membrane in choroid plexus. Therefore, they expect to find the same mechanisms in humans.

As a next step, they will try to determine how the inflow of water to the brain can be affected and controlled using the newly discovered mechanism.

Schematic drawing of transporters in a choroid plexus epithelial cell.

Schematic drawing of transporters in a choroid plexus epithelial cell.
(a) The drawing depicts the selective expression of NKCC1 at the luminal membrane and indicates its unique outward transport direction, due to the high intracellular concentration of Na+ and Cl− in this tissue (ion concentrations given in mM).
The NKCC1-mediated cotransport of water is indicated with a dashed arrow. The Na+/K+-ATPase and AQP114 are indicated on the luminal membrane of the choroid plexus epithelium (CPE), while KCC1 is localized to the basolateral membrane facing the vascular compartment (this study).
(b) The drawing includes the many other coupled transporters localized to the choroidal epithelial membranes1.
Note that NCBE may also be referred to as NBCn2
Credit: Annette B. Steffensen et al, CC-BY

The study is based on tests in animals, so it has less statistical weight than case/control studies in humans and larger randomized trials in humans.

ThE work was supported by Thorberg’s Foundation, Novo Nordisk Foundation; Tandem program, the Danish Medical Research Council, Sapere Aude program, Vera and Carl Johan Michaelsen’s Scholarship, the Augustinus Foundation, Doctor Sofus Carl Emil Friis og hustru Olga Doris Friis’ scholarship, and the Carlsberg Foundation.

Annette B. Steffensen, Eva K. Oernbo, Anca Stoica, Niklas J. Gerkau, Dagne Barbuskaite, Katerina Tritsaris, Christine R. Rose & Nanna MacAulay
Cotransporter-mediated water transport underlying cerebrospinal fluid formation
Nature Communications volume 9, Article number: 2167 (2018)

Top Image: University of Copenhagen