Aquaporin 1 and the Na+/K+/2Cl− cotransporter 1 are present in the leptomeningeal vasculature of the adult rodent central nervous system

Abstract

Background: The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source. Although previous studies indicate that part of CSF production occurs in the subarachnoid space (SAS), the mechanisms underlying extra-choroidal CSF production remain elusive. We here investigated the distributions of aquaporin 1 (AQP1) and Na + /K + /2Cl − cotransporter 1 (NKCC1), key proteins for choroidal CSF production, in the adult rodent brain and spinal cord. Methods: We have accessed AQP1 distribution in the intact brain using uDISCO tissue clearing technique and by Western blot. AQP1 and NKCC1 cellular localization were accessed by immunohistochemistry in brain and spinal cord obtained from adult rodents. Imaging was performed using light-sheet, confocal and bright field light microscopy. Results: We determined that AQP1 is widely distributed in the leptomeningeal vasculature of the intact brain and that its glycosylated isoform is the most prominent in different brain regions. Moreover, AQP1 and NKCC1 show specific distributions in the smooth muscle cell layer of penetrating arterioles and veins in the brain and spinal cord, and in the endothelia of capillaries and venules, restricted to the SAS vasculature. Conclusions: Our results shed light on the molecular framework that may underlie extra-choroidal CSF production and we propose that AQP1 and NKCC1 within the leptomeningeal vasculature, specifically at the capillary level, are poised to play a role in CSF production throughout the central nervous system.

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development

“…We adapted our tool from clinical practice to provide a range of options for measuring global cerebral fluid states that reflect the interaction between CSF and cranial tissues. In later life, CSF homeostasis is maintained by collaborative efforts from multiple putative players in the brain, including the ChP, the dural lymphatics 14 , leptomeningeal vasculature 77 , and the ependyma 78 . While this approach measures overall cranial fluid dynamics as one single unit, future applications could apply mathematical models that have been proposed to isolate the contribution of distinct CSF outflow routes using data acquired from patients 79 .…”

Novel therapeutics for hydrocephalus: Insights from animal models

“…AQP1 is mainly expressed on the apical and basolateral surfaces of the choroid plexuses and plays a role in CSF production 100 . Acetazolamide may reduce CSF production by inhibiting AQP1 and thus slow the development of hydrocephalus.…”

“…AQP1 is mainly expressed on the apical and basolateral surfaces of the choroid plexuses and plays a role in CSF production. 100 Acetazolamide may reduce CSF production by inhibiting AQP1 and thus slow the development of hydrocephalus. However, a study in six dogs with internal hydrocephalus showed that acetazolamide treatment was not effective in inhibiting ventricular dilation.…”

Organic solvent‐based tissue clearing techniques and their applications

“…They found that AQP1 is expressed in the vasculature of the adult rodent brain. The results shed new light on extrachoroidal cerebrospinal fluid production [62].…”