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

Huixin Xu,Benjamin C Warf,Amanda Vernon,Michael J Holtzman,Christopher Naranjo,Cameron Sadegh,Fan Gao,Pei-Yi Lin,Frederick B Shipley,Jin Cui,Della Syau Della Syau,Ryann M Fame,Yong Zhang,Maria K Lehtinen,Jason Sutin,Myriam Heiman

doi:10.1038/s41467-020-20666-3

Abstract

Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K+, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K+ transporters, particularly the Na+, K+, Cl−, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K+ clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K+ clearance through the ChP in the critical period during postnatal neurodevelopment in mice.

Highlights

Cerebrospinal fluid (CSF) provides vital support for the brain
We found that choroid plexus (ChP) NKCC1 OE reduced CSF [K+] more than controls, with their P1 CSF [K+] values closely approximating those normally observed at P7 (Fig. 4j), indicating accelerated K+ clearance from CSF after enhanced ChP NKCC1 activity
We sought to understand how CSF is cleared from the brain during a period of development prior to the maturation of CSF outflow routes suggested to exist in adults[1,8,11,12,13,14,56]

Summary

Introduction

Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. Our results implicate NKCC1 in regulating CSF K+ clearance through the ChP in the critical period during postnatal neurodevelopment in mice. Often schizophrenia patients have enlarged lateral ventricles by their first episode of psychosis[4], in some cases as early as infancy[5], suggesting a role for CSF clearance abnormalities in this and possibly other neurodevelopmental disorders As another example, autism spectrum disorders are associated with altered CSF distribution patterns and enlarged CSF space surrounding the brain[6]. The choroid plexus (ChP) is an intraventricular epithelial structure that forms the majority of the blood-CSF barrier and emerges prenatally It contains diverse ion and fluid transporters along its vast surface area[15]. Broad transcriptional changes of the machinery regulating fluid/ion transport support the concept of temporally dynamic and possibly context-dependent ChP functions in determining net directionality of CSF transport[23,24]

Methods

Results

Conclusion