Long-term potentiation (LTP) depends on the coordinated regulation of an ensemble of proteins related to Ca2+ homeostasis, including Ca2+ transporters. One of the major players in the regulation of intracellular Ca2+ ([Ca2+]i) homeostasis in neurons is the sodium/calcium exchanger (NCX), which represents the principal mechanism of Ca2+ clearance in the synaptic sites of hippocampal neurons. Because NCX3, one of the three brain isoforms of the NCX family, is highly expressed in the hippocampal subfields involved in LTP, we hypothesized that it might represent a potential candidate for LTP modulation. To test this hypothesis, we first examined the effect of ncx3 gene ablation on NCX currents (INCX) and Ca2+ homeostasis in hippocampal neurons. ncx3-/- neurons displayed a reduced INCX, a higher basal level of [Ca2+]i, and a significantly delayed clearance of [Ca2+]i following depolarization. Furthermore, measurement of field EPSPs, recorded from the CA1 area, revealed that ncx3-/- mice had an impaired basal synaptic transmission. Moreover, hippocampal slices from ncx3-/- mice exhibited a worsening in LTP compared with congenic ncx3-/-. Consistently, immunohistochemical and immunoblot analysis indicated that in the hippocampus of ncx3-/- mice both Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) expression and the phosphoCaMKIIα/CaMKIIα ratio were significantly reduced compared with ncx3-/-. Interestingly, ncx3-/- mice displayed a reduced spatial learning and memory performance, as revealed by the novel object recognition, Barnes maze, and context-dependent fear conditioning assays. Collectively, our findings demonstrate that the deletion of the ncx3 gene in mice has detrimental consequences on basal synaptic transmission, LTP regulation, spatial learning, and memory performance.
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