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

• Published in: Nature communications Vol. 12; no. 1; p. 447
• Main Authors: Xu, Huixin, Fame, Ryann M., Sadegh, Cameron, Sutin, Jason, Naranjo, Christopher, Della Syau, Cui, Jin, Shipley, Frederick B., Vernon, Amanda, Gao, Fan, Zhang, Yong, Holtzman, Michael J., Heiman, Myriam, Warf, Benjamin C., Lin, Pei-Yi, Lehtinen, Maria K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/51; 14/19; 14/28; 38/77; 38/91; 42/109; 42/44; 59/57; 631/136; 631/378/1689; 631/378/2571; 64/60; Accumulation; Animals; Animals, Newborn; ATP; Brain; Cerebrospinal fluid; Cerebrospinal Fluid - metabolism; Chloride transport; Choroid plexus; Choroid Plexus - diagnostic imaging; Choroid Plexus - growth & development; Choroid Plexus - metabolism; Choroid Plexus - pathology; Critical period; Dependovirus - genetics; Disease Models, Animal; Embryo, Mammalian; Female; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humanities and Social Sciences; Humans; Hydrocephalus; Hydrocephalus - congenital; Hydrocephalus - diagnosis; Hydrocephalus - pathology; Hydrocephalus - physiopathology; Injections, Intraventricular; Intracranial pressure; Intracranial Pressure - physiology; Magnetic Resonance Imaging; Male; Mice; Mice, Transgenic; multidisciplinary; Neurodevelopment; Science; Science (multidisciplinary); Solute Carrier Family 12, Member 2 - genetics; Solute Carrier Family 12, Member 2 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20666-3

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. Abnormal CSF accumulation in the brain can lead to hydrocephalus. The mechanisms regulating CSF clearance during early development are unclear. Here, the authors show that NKCC1 regulates the clearance of both CSF K + and fluid volume through the choroid plexus during postnatal development in mice.