TY - ABST

T1 - The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates cerebrospinal fluid pH

AU - Barbuskaite, Dagne

AU - Praetorius, Jeppe

AU - Christensen, Henriette L.

AU - Rojek, Alexandra

AU - Nielsen, Hans Malte

AU - Fuchtbauer, Ernst-Martin

AU - Wang, Tobias

AU - Damkier, Helle Hasager

PY - 2017

Y1 - 2017

N2 - Respiratory centers in the central nervous system (CNS) react to changes in pCO2 and maintain systemic acid/base homeostasis by controlling the rate and depth of respiration. Both blood-brain barrier and blood-CSF barrier are highly permeable to CO2 enabling swift transmission of arterial pCO2 fluctuations to be coupled with CSF pH changes, whilst both barriers are much less permeable to H+ and HCO3−, hence masking the effects of metabolic acid-base disturbances. The electrogenic Na+-HCO3− cotransporter NBCe2 is expressed in the CSF-facing plasma membrane of the choroid plexus epithelial (CPE) cells and could be a regulator of CSF pH. We hypothesized that NBCe2 is responsible for HCO− extrusion into the ventricle lumen to counteract decreases in CSF pH during acidosis. Intracellular pH (pHi) measurements on CPE cells from NBCe2 knockout (KO) mice showed a statistically significant 84% increase in Na+-dependent acid extrusion following intracellular acidification by ammonium chloride prepulse and an 81% reduction in DIDS-sensitive base efflux after intracellular alkalization by trimethylamine. Knockout of NBCe2 abolished CSF pH recovery from hypercapnia-induced acidosis compared to control mice: wt (n=5): 0.0048 ± 0.003 vs ko (n=6): −0.0001±0.0002 pH units/min, p=0.0043. Choroid plexus targeted NBCe2 knockdown mice generated by intracerebroventricular installation of siRNA revealed a similar effect: Control (n=5): 0.002+/−0.0004 vs. NBCe2 knockdown (n=7): −0.0001±0.0007, p=0.047. Knockout of NBCe2 did not affect respiration rate or tidal volume compared to wildtype, and revealed a similar ventilatory response as controls when exposed to 5% CO2. In conclusion, we show that NBCe2 is important for recovery of CSF pH after CO2 induced acidosis by transporting HCO3− into the CSF. This suggests a significant role for NBCe2 in regulating brain pH when faced with an acid challenge independent of the respiratory response.

AB - Respiratory centers in the central nervous system (CNS) react to changes in pCO2 and maintain systemic acid/base homeostasis by controlling the rate and depth of respiration. Both blood-brain barrier and blood-CSF barrier are highly permeable to CO2 enabling swift transmission of arterial pCO2 fluctuations to be coupled with CSF pH changes, whilst both barriers are much less permeable to H+ and HCO3−, hence masking the effects of metabolic acid-base disturbances. The electrogenic Na+-HCO3− cotransporter NBCe2 is expressed in the CSF-facing plasma membrane of the choroid plexus epithelial (CPE) cells and could be a regulator of CSF pH. We hypothesized that NBCe2 is responsible for HCO− extrusion into the ventricle lumen to counteract decreases in CSF pH during acidosis. Intracellular pH (pHi) measurements on CPE cells from NBCe2 knockout (KO) mice showed a statistically significant 84% increase in Na+-dependent acid extrusion following intracellular acidification by ammonium chloride prepulse and an 81% reduction in DIDS-sensitive base efflux after intracellular alkalization by trimethylamine. Knockout of NBCe2 abolished CSF pH recovery from hypercapnia-induced acidosis compared to control mice: wt (n=5): 0.0048 ± 0.003 vs ko (n=6): −0.0001±0.0002 pH units/min, p=0.0043. Choroid plexus targeted NBCe2 knockdown mice generated by intracerebroventricular installation of siRNA revealed a similar effect: Control (n=5): 0.002+/−0.0004 vs. NBCe2 knockdown (n=7): −0.0001±0.0007, p=0.047. Knockout of NBCe2 did not affect respiration rate or tidal volume compared to wildtype, and revealed a similar ventilatory response as controls when exposed to 5% CO2. In conclusion, we show that NBCe2 is important for recovery of CSF pH after CO2 induced acidosis by transporting HCO3− into the CSF. This suggests a significant role for NBCe2 in regulating brain pH when faced with an acid challenge independent of the respiratory response.

M3 - Conference abstract in journal

VL - 31

JO - F A S E B Journal

JF - F A S E B Journal

SN - 0892-6638

IS - S1

M1 - 702.4

ER -