TY - JOUR
T1 - Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development
AU - Xu, Huixin
AU - Fame, Ryann M.
AU - Sadegh, Cameron
AU - Sutin, Jason
AU - Naranjo, Christopher
AU - Della Syau, Syau
AU - Cui, Jin
AU - Shipley, Frederick B.
AU - Vernon, Amanda
AU - Gao, Fan
AU - Zhang, Yong
AU - Holtzman, Michael J.
AU - Heiman, Myriam
AU - Warf, Benjamin C.
AU - Lin, Pei Yi
AU - Lehtinen, Maria K.
N1 - Funding Information:
We thank members of the Lehtinen, Heiman, and Warf labs for helpful discussions; Nancy Chamberlin for advice on the manuscript; Katia Georgopoulos for sharing the Chd4 fl/fl mouse line and associated genotyping methods; P. Ellen Grant for the ICP monitor. We thank the following facilities and personnel: Maria Ericsson and HMS EM facility; Yaotang Wu and Michael Marcotrigiano and BCH Small Animal Imaging Laboratory; the MIT BioMicro Center (TRAP sequencing); BCH viral core and University of Pennsylvania Vector Core; the IDDRC Cellular Imaging Core and Harvard Digestive Diseases Center Imaging Core. NIH T32 HL110852 (R.M.F. and J.C.); William Randolph Hearst Fund (J.C.); NSF Graduate Research Fellowship Program (F.B.S.); OFD/BTREC/CTREC Faculty Development Fellowship Award (R.M.F.); Simons Foundation Autism Research Awards (IDs 590293 and 645596 for C.N. and D.S., respectively). NIH R01 AI130591 and R35 HL145242 (M.J.H.); NIH R00 HD083512 (P.-Y.L.); and R01 HD096693 (P.-Y.L. and B.C.W.); BCH Pilot Grant, Pediatric Hydrocephalus Foundation, Hydrocephalus Association, Human Frontier Science Program (HFSP) research program grant #RGP0063/2018, NIH R01 NS088566, the New York Stem Cell Foundation (M.K. L.); BCH IDDRC 1U54HD090255 and BCH viral core P30EY012196. M.K.L. is a New York Stem Cell Foundation—Robertson Investigator.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099534238&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-20666-3
DO - 10.1038/s41467-020-20666-3
M3 - Article
C2 - 33469018
AN - SCOPUS:85099534238
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 447
ER -