The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pH

Area of Science:

• Neuroscience
• Physiology
• Molecular Biology

Background:

• Normal brain function depends on stable cerebrospinal fluid (CSF) pH.
• Disorders causing high blood CO2 (hypercapnia) decrease brain pH, potentially harming the brain.
• The choroid plexus epithelium (CPE) produces CSF and is hypothesized to regulate its pH.

Purpose of the Study:

• To investigate the role of the electrogenic sodium bicarbonate cotransporter 2 (NBCe2) in CSF pH regulation by the CPE.
• To determine if NBCe2 is essential for normalizing CSF pH during hypercapnia-induced acidosis.

Main Methods:

• Generated and validated NBCe2 (Slc4a5) knockout (KO) mice.
• Assessed base extrusion rates in CPE cells from NBCe2 KO and control mice.
• Measured CSF pH recovery in NBCe2 KO and wild-type mice during hypercapnia and CO2 exposure.
• Evaluated ventilatory responses and seizure susceptibility in NBCe2 KO mice.

Main Results:

• NBCe2 KO mouse CPE cells showed a 77% reduction in base extrusion rate.
• NBCe2 KO mice exhibited an 85-90% reduction in CSF pH recovery during hypercapnia.
• NBCe2 deficiency did not alter baseline respiration or ventilatory response to CO2.
• NBCe2 KO mice did not show altered seizure development.

Conclusions:

• The CPE is crucial for CSF pH regulation, particularly during acidosis.
• The NBCe2 transporter in the CPE is indispensable for restoring CSF pH after hypercapnia.
• This finding clarifies molecular mechanisms of CSF pH homeostasis in conditions like chronic lung disease.