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

Silvia Natale, Serenella Anzilotti, Tiziana Petrozziello, Roselia Ciccone, Angelo Serani, Lucrezia Calabrese, Beatrice Severino, Francesco Frecentese, Agnese Secondo, Anna Pannaccione, Ferdinando Fiorino, Ornella Cuomo, Antonio Vinciguerra, Lucia D’Esposito, Adolfo Gustavo Sadile, Simona Cabib, Gianfranco Di Renzo, Lucio Annunziato, Pasquale Molinaro

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2358-2376
Number of pages19
JournalMolecular Neurobiology
Volume57
Issue number5
DOIs
Publication statusPublished - May 1 2020

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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