Abstract
BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source
Aquaporin 1 is widely expressed in the adult rodent brain in its glycosylated and non‐glycosylated forms Using light-sheet microscopy we assessed the distribution of aquaporin 1 (AQP1) in the intact adult mouse brain (P60; n = 4) upon Ultimate three-Dimensional Imaging of Solvent-Cleared Organs (uDISCO) tissue clearing technique
The use of an antibody that recognizes an epitope in the intracellular domain of AQP1 (AQP1int) revealed immunoreactive cells in the subarachnoid cisterns adjacent to the cerebellum, in the leptomeningeal vasculature, notably along the middle cerebral arteries (MCAs), and in the olfactory bulb (Fig. 1a)
Summary
The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source. Previous studies indicate that part of CSF production occurs in the subarachnoid space (SAS), the mechanisms underlying extra-choroidal CSF production remain elusive. Li et al Fluids Barriers CNS (2020) 17:15 studies have suggested that some fraction of CSF production must occur outside the ventricular system in mammals, at the subarachnoid space (SAS) [18,19,20]. That approach gives only a coarse indication of the cellular site and mechanisms underlying extra-choroidal CSF production. The high content of mitochondria might support active transport of ions at the blood–brain barrier (BBB), which in turn triggers water fluxes, in a manner resembling the mechanism underlying CSF secretion by the choroid plexus. The hypothesis that the BBB is a source of CSF presently lacks substantiation from functional studies [29]
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