Membrane transporters control cerebrospinal fluid formation independently of conventional osmosis to modulate intracranial pressure

BACKGROUND: Disturbances in the brain fluid balance can lead to life-threatening elevation in the intracranial pressure (ICP), which represents a vast clinical challenge. Nevertheless, the details underlying the molecular mechanisms governing cerebrospinal fluid (CSF) secretion are largely unresolved, thus preventing targeted and efficient pharmaceutical therapy of cerebral pathologies involving elevated ICP. METHODS: Experimental rats were employed for in vivo determinations of CSF secretion rates, ICP, blood pressure and ex vivo excised choroid plexus for morphological analysis and quantification of expression and activity of various transport proteins. CSF and blood extractions from rats, pigs, and humans were employed for osmolality determinations and a mathematical model employed to determine a contribution from potential local gradients at the surface of choroid plexus. RESULTS: We demonstrate that CSF secretion can occur independently of conventional osmosis and that local osmotic gradients do not suffice to support CSF secretion. Instead, the CSF secretion across the luminal membrane of choroid plexus relies approximately equally on the Na(+)/K(+)/2Cl(−) cotransporter NKCC1, the Na(+)/HCO(3)(−) cotransporter NBCe2, and the Na(+)/K(+)-ATPase, but not on the Na(+)/H(+) exchanger NHE1. We demonstrate that pharmacological modulation of CSF secretion directly affects the ICP. CONCLUSIONS: CSF secretion appears to not rely on conventional osmosis, but rather occur by a concerted effort of different choroidal transporters, possibly via a molecular mode of water transport inherent in the proteins themselves. Therapeutic modulation of the rate of CSF secretion may be employed as a strategy to modulate ICP. These insights identify new promising therapeutic targets against brain pathologies associated with elevated ICP. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-022-00358-4.