Age-appropriate potassium clearance from perinatal cerebrospinal fluid depends on choroid plexus NKCC1

Abstract

Regulation of the volume and electrolyte composition of the cerebrospinal fluid (CSF) is vital for brain development and function. The Na-K-Cl co-transporter NKCC1 in the choroid plexus (ChP) plays key roles in regulating CSF volume by co-transporting ions and mediating same-direction water movements. Our previous study showed ChP NKCC1 is highly phosphorylated in neonatal mice as the CSF K+ level drastically decreases and that overexpression of NKCC1 in the ChP accelerates CSF K+ clearance and reduces ventricle size [1]. These data suggest that NKCC1 mediates CSF K+ clearance following birth in mice. In this current study, we used CRISPR technology to create a conditional NKCC1 knockout mouse line and evaluated CSF K+ by Inductively Coupled Plasma Optical Emission spectroscopy (ICP-OES). We demonstrated ChP-specific reduction of total and phosphorylated NKCC1 in neonatal mice following embryonic intraventricular delivery of Cre recombinase using AAV2/5. ChP-NKCC1 knockdown was accompanied by a delayed perinatal clearance of CSF K+. No gross morphological disruptions were observed in the cerebral cortex. We extended our previous results by showing embryonic and perinatal rats shared key characteristics with mice, including decreased ChP NKCC1 expression level, increased ChP NKCC1 phosphorylation state, and increased CSF K+ levels compared to adult. Collectively, these follow up data support ChP NKCC1’s role in age-appropriate CSF K+ clearance during neonatal development.

Postnatal meningeal CSF transport is primarily mediated by the arachnoid and pia maters and is not altered after intraventricular hemorrhage-posthemorrhagic hydrocephalus

“…Other studies have indicated that CSF may be transported across a normally functioning tela choroidea into the ChP and ventricles as a regular aspect of brain physiology [ 20 , 51 ]. The results of this present study support these findings and build upon previous studies implicating the ChP in direct CSF solute transport [ 54 , 55 ]. Future studies should map the timeline of CSF tracer distribution along the tela choroidea and LV, 3V, and 4V ChP in vivo.…”

Understanding and Modeling the Pathophysiology of Hydrocephalus: In Search of Better Treatment Options

“…For a synopsis of the controversy surrounding the directionality of the flux, the reader is referred to a point-counterpoint exchange in the Journal of Physiology [109][110][111][112]. More recently, data suggest that the direction of electrolyte movement may be heavily influenced by local ion concentrations [113] or the developmental stage [114]. It was previously reported that around 600 molecules could be moved by NKCC1 [115], but recent studies suggest that the transporter only moves around 86 water molecules [116].…”