Identification of the role played by Na+/Ca2+ exchanger 1 (NCX1) in hippocampal dependent anxiety, spatial learning and memory consolidation through genetic modified mice and newly synthesized compounds.

The Na+/Ca2+ exchanger 1 (NCX1), which is highly expressed in the hippocampus, cortex, and amygdala, regulates Akt1 phosphorylation. Since Akt1 is part of the PTEN/Akt1/CREB signaling pathway, which participates in synaptic plasticity and long-term memory, we investigated whether NCX1 expression/activity might also be involved in some hippocampal-dependent learning and memory processes. To test this hypothesis, we used two genetically-modified mice to selectively overexpress (NCX1.4over) or downregulate (NCX1ko) NCX1 in hippocampal, cortical, and amygdala neurons and a newly synthesized selective NCX1 stimulating compound, named CN-PYB2. Both NCX1.4over and CN-PYB2-treated mice showed increased phosphorylated CaMKII levels in the hippocampus and improved long-term spatial learning and memory performance. By contrast, NCX1ko mice displayed a decrease in both. In addition, both NCX1.4over and CN-PYB2-treated mice also displayed an increase in context-dependent anxiety. Altogether, these results demonstrate that neuronal NCX1 participates in hippocampal-amygdala memory consolidation and promote anxiety behavior.