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

Huixin Xu, Ryann M. Fame, Cameron Sadegh, Jason Sutin, Christopher Naranjo, Syau, Jin Cui, Frederick B. Shipley, Amanda Vernon, Fan Gao, Yong Zhang, Michael J. Holtzman, Myriam Heiman, Benjamin C. Warf, Pei-Yi Lin and Maria K. Lehtinen ()
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Huixin Xu: Boston Children’s Hospital
Ryann M. Fame: Boston Children’s Hospital
Cameron Sadegh: Boston Children’s Hospital
Jason Sutin: Boston Children’s Hospital, Harvard Medical School
Christopher Naranjo: Harvard Medical School
Syau: Harvard Medical School
Jin Cui: Boston Children’s Hospital
Frederick B. Shipley: Boston Children’s Hospital
Amanda Vernon: Broad Institute of MIT and Harvard
Fan Gao: Broad Institute of MIT and Harvard
Yong Zhang: Washington University
Michael J. Holtzman: Washington University
Myriam Heiman: Broad Institute of MIT and Harvard
Benjamin C. Warf: Boston Children’s Hospital
Pei-Yi Lin: Boston Children’s Hospital, Harvard Medical School
Maria K. Lehtinen: Boston Children’s Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20666-3

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