Abstract
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.
Funder
American Historical Association
Emory University | University Research Committee, Emory University
Publisher
Springer Science and Business Media LLC
Reference52 articles.
1. Ruffin, V. A., Salameh, A. I., Boron, W. F. & Parker, M. D. Intracellular pH regulation by acid-base transporters in mammalian neurons. Frontiers in physiology 5,
http://www.ncbi.nlm.nih.gov/pubmed/24592239
(2014).
2. Katsura, K. & Siesjo, B. K. In pH and Brain Function (eds Kaila, K. & Ransom, B.R.) 563–582 (Wiley-Liss, Inc, 1998).
3. Bevensee, M. O., Alper, S. L., Aronson, P. S. & Boron, W. F. In The Kidney, Physiology and Pathophysiology (eds Seldin, D.W. & Giebisch, G.) 391–442 (Raven, 2000).
4. Lipton, P. Ischemic cell death in brain neurons. Physiol Rev. 79, 1431–1568 (1999).
5. Chesler, M. Regulation and modulation of pH in the brain. Physiological reviews 83, 1183–1221 (2003).
Cited by
13 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献