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Author Notes:

Correspondence to Inyeong Choi, ichoi@emory.edu

I.C. designed the study and wrote the manuscript.

H.P. performed most of the experiments.

C.G. performed electrophysiology experiments, H.P. and Y.K. performed immunofluorescence, and J.L. coordinated data collection and performed statistical analysis.

All authors contributed to data analysis and interpretation.

We would like to thank Jayre Jones for technical support for mouse handling and care, and Rosa Kim for editing the manuscript.

We also thank Dr. Walter Boron and Gerald Babcock for providing NCBE and NDCBE antibodies.

The authors declare no competing interests.

Subjects:

Research Funding:

NIH GM078502

American Heart Association 14GRNT20480379

Emory University Research Committee (I.C)

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • COTRANSPORTER NBCN1
  • TARGETED DISRUPTION
  • CELL-DEATH
  • EXCHANGER
  • PH
  • GENE
  • LOCALIZATION
  • EXPRESSION
  • EPILEPSY
  • NETWORK

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

Tools:

Journal Title:

Scientific Reports

Volume:

Volume 9, Number 1

Publisher:

, Pages 15981-15981

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2019, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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