Deletion of the Na/HCO3 Transporter NBCn1 Protects Hippocampal Neurons from NMDA-induced Seizures and Neurotoxicity in Mice

• Type of Material: Article
• Authors: Hae Jeong Park, Kyung Hee University; Carlos Gonzalez Islas, Emory University; Yunhee Kang, Emory University; Jun Ming Li, Emory University; Inyeong Choi, Emory University
• Language: English
• Date: 2019-11-05
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-52413-0
• Title of Journal or Parent Work: Scientific Reports
• Volume: 9
• Issue: 1
• Start Page: 15981
• End Page: 15981
• Grant/Funding Information: NIH GM078502; American Heart Association 14GRNT20480379; Emory University Research Committee (I.C)
• Keywords: LOCALIZATION; Science & Technology; NETWORK; PH; COTRANSPORTER NBCN1; EXCHANGER; Multidisciplinary Sciences; Science & Technology - Other Topics; EPILEPSY; CELL-DEATH; TARGETED DISRUPTION; GENE; EXPRESSION
• Research Categories: Biology, Genetics; Health Sciences, Pharmacology

Abstract

The Na/HCO3 cotransporter NBCn1/SLC4A7 can affect glutamate neurotoxicity in primary cultures of rat hippocampal neurons. Here, we examined NMDA-induced neurotoxicity in NBCn1 knockout mice to determine whether a similar effect also occurs in the mouse brain. In primary cultures of hippocampal neurons from knockouts, NMDA had no neurotoxic effects, determined by lactate dehydrogenase release and nitric oxide synthase (NOS)-dependent cGMP production. Male knockouts and wildtypes (6–8 weeks old) were then injected with NMDA (75 mg/kg; ip) and hippocampal neuronal damages were assessed. Wildtypes developed severe tonic-clonic seizures, whereas knockouts had mild seizure activity (motionless). In knockouts, the NOS activity, caspase-3 expression/activity and the number of TUNEL-positive cells were significantly low. Immunochemical analysis revealed decreased expression levels of the NMDA receptor subunit GluN1 and the postsynaptic density protein PSD-95 in knockouts. Extracellular recording from hippocampal slices showed no Mg2+/NMDA-mediated epileptiform events in knockouts. In conclusion, these results show a decrease in NMDA neurotoxicity by NBCn1 deletion. Given that acid extrusion has been known to prevent pH decrease and protect neurons from acid-induced damage, our study presents novel evidence that acid extrusion by NBCn1 stimulates neurotoxicity.