RT Journal Article
SR Electronic
T1 Na<sup>+</sup>–Ca<sup>2+</sup> Exchanger (NCX3) Knock-Out Mice Display an Impairment in Hippocampal Long-Term Potentiation and Spatial Learning and Memory
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7312
OP 7321
DO 10.1523/JNEUROSCI.6296-10.2011
VO 31
IS 20
A1 Pasquale Molinaro
A1 Davide Viggiano
A1 Robert Nisticò
A1 Rossana Sirabella
A1 Agnese Secondo
A1 Francesca Boscia
A1 Anna Pannaccione
A1 Antonella Scorziello
A1 Bisan Mehdawy
A1 Sophie Sokolow
A1 André Herchuelz
A1 Gianfranco F. Di Renzo
A1 Lucio Annunziato
YR 2011
UL http://www.jneurosci.org/content/31/20/7312.abstract
AB 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.