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.
Highlights
The pH in the brain extracellular space and cerebrospinal fluid is normally maintained at pH 7.3, but it can be substantially low under some pathological conditions[1,2,3,4]
Www.nature.com/scientificreports with N-methyl-D-aspartic acid receptor (NMDAR) via the postsynaptic density protein PSD-95 to form a large protein complex[11,15]. These results suggest that NBCn1 and NMDAR would coordinate together in a manner that NBCn1 upregulation under acidic conditions enhances NMDAR presentation in membranes and as a result cell death increases
We examined NMDA-induced neurotoxicity in NBCn1 knockout (KO) mice to determine whether a similar coordination occurs in the mouse brain
Summary
The pH in the brain extracellular space and cerebrospinal fluid is normally maintained at pH 7.3, but it can be substantially low under some pathological conditions[1,2,3,4]. A mildly low pH can protect cells from damage as it inhibits numerous proteins responsible for membrane discharge, synaptic transmission and signal transduction[5] One of these proteins is the N-methyl-D-aspartic acid receptor (NMDAR) that causes cell death upon excessive or prolonged exposure to glutamate[6]. NBCn1 can cluster www.nature.com/scientificreports with NMDAR via the postsynaptic density protein PSD-95 to form a large protein complex[11,15] These results suggest that NBCn1 and NMDAR would coordinate together in a manner that NBCn1 upregulation under acidic conditions enhances NMDAR presentation in membranes and as a result cell death increases. The results imply that NBCn1 can be a target for neuroprotection from acidosis-related brain damage
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