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Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory


The Na+/Ca2+ exchanger 1 (NCX1) participates in the maintenance of neuronal Na+ and Ca2+ homeostasis, and it is highly expressed at synapse level of some brain areas involved in learning and memory processes, including the hippocampus, cortex, and amygdala. Furthermore, NCX1 increases Akt1 phosphorylation and enhances glutamate-mediated Ca2+ influx during depolarization in hippocampal and cortical neurons, two processes involved in learning and memory mechanisms. We investigated whether the modulation of NCX1 expression/activity might influence learning and memory processes. To this aim, we used a knock-in mouse overexpressing NCX1 in hippocampal, cortical, and amygdala neurons (ncx1.4over) and a newly synthesized selective NCX1 stimulating compound, named CN-PYB2. Both ncx1.4over and CN-PYB2-treated mice showed an amelioration in spatial learning performance in Barnes maze task, and in context-dependent memory consolidation after trace fear conditioning. On the other hand, these mice showed no improvement in novel object recognition task which is mainly dependent on non-spatial memory and displayed an increase in the active phosphorylated CaMKIIα levels in the hippocampus. Interestingly, both of these mice showed an increased level of context-dependent anxiety.

Altogether, these results demonstrate that neuronal NCX1 participates in spatial-dependent hippocampal learning and memory processes.

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We thank Paola Merolla for the editorial revision of the manuscript. This work was supported by Futuro in Ricerca MIUR (RBFR13M6FN) to P.M.; PRIN 2015 MIUR (2015BEX2BR_003) to P.M.; PRIN 2017 MIUR (2017WJZ9W9_004); POR RarePlatNET from Regione Campania to L.A.; Programma Operativo Nazionale (PON_01602 and PON03PE_00146_1) from MIUR to L.A.; POR Campania FESR 2007-2013 OCKEY (B25C13000280007) to G.D.R.; POR Campania FESR 2007-2013 MOVIE (B25C1300024007) to L.A.

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Conceptualization: P.M. Methodology: P.M. and S.N. Formal analysis: P.M. Investigation: S.N., P.M., S.A., T.P., R.C., A.Ser., L.C., A.Sec., A.P. Resources: B.S., F.Fre., F.Fio., O.C., A.V. Data curation: P.M., S.N., L.D.E. Writing—original draft: P.M. Writing—review and editing: A.G.S., S.C., G.D.R., L.A. Visualization: P.M. Project administration: P.M. Funding acquisition: P.M. and L.A.

Correspondence to Lucio Annunziato or Pasquale Molinaro.

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Supplemental Fig. 1

pCREB S133 level is increased in the hippocampus of ncx1.4over mice. (a, b) Immunofluorescence images showing pCREB_S133 immunosignal in ventral (a) and dorsal (b) hippocampal regions of ncx1+/+ and ncx1.4over mice. Overview pictures and high-magnification photomicrographs showing the colocalization of NeuN (green—a, e) and pCREB_S133 (red—b, f) in the ventral or dorsal hippocampus. Scale bars, 200 μm or 25 μm. (c) Quantification of pCREB_S133 immunosignals in the ventral and dorsal hippocampus of ncx1.4+/+ and ncx1.4over mice (60 neurons from 3 mice for each group). *p < 0.05 vs. the corresponding congenic ncx1.4+/+ mouse group, unpaired Student’s t test. (d) Representative Western blots and quantifications of pCREB_S133 in the hippocampus of ncx1.4+/+ (n = 8) and ncx1.4over (n = 8) mice. Data were normalized for CREB immunosignal and expressed as percentages of corresponding control group. *p < 0.05 vs. congenic wild-type mouse group, unpaired Student t test (PNG 682 kb)

Supplemental Fig. 2

Proposed model of enhanced hippocampal-dependent learning and memory in ncx1.4over and CN-PYB2-treated mice. Glutamate, the main neurotransmitter involved in synaptic plasticity, opens the AMPA receptors causing (1) the collapse of the Na+ gradient, (2) the depolarization of plasma membrane voltage, (3) the activation of NMDA receptors, and (4) the stimulation of the reverse mode of NCX1 enhancing NMDA-dependent Ca2+ influx. This enhanced Ca2+ influx facilitates the activation of several [Ca2+]i-dependent mechanisms of synaptic plasticity including CaMKIIα and Akt1 and their target proteins (PNG 413 kb)

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Natale, S., Anzilotti, S., Petrozziello, T. et al. Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory. Mol Neurobiol (2020). https://doi.org/10.1007/s12035-020-01888-4

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  • Synaptic plasticity
  • Long-term memory
  • Drug discovery
  • Anxiety