Genetically modified mice as a strategy to unravel the role played by the Na+/Ca2+ exchanger in brain ischemia and in spatial learning and memory deficits

Pasquale Molinaro, Mauro Cataldi, Ornella Cuomo, Davide Viggiano, Giuseppe Pignataro, Rossana Sirabella, Agnese Secondo, Francesca Boscia, Anna Pannaccione, Antonella Scorziello, Sophie Sokolow, André Herchuelz, Gianfranco Di Renzo, Lucio Annunziato

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Because no isoform-specific blocker of NCX has ever been synthesized, a more selective strategy to identify the role of each antiporter isoform in the brain was represented by the generation of knockout and knockin mice for the different isoforms of the antiporter. Experiments performed in NCX2 and NCX3 knockout mice provided evidence that these two isoforms participate in spatial learning and memory consolidation, although in an opposite manner. These new data from ncx2-/- and ncx3-/- mice may open new experimental avenues for the development of effective therapeutic compounds that, by selectively inhibiting or activating these molecular targets, could treat patients affected by cognitive impairment including Alzheimer's, Parkinson's, Huntington's diseases, and infarct dementia. More importantly, knockout and knockin mice also provided new relevant information on the role played by NCX in maintaining the intracellular Na+ and Ca2+ homeostasis and in protecting neurons during brain ischemia. In particular, both ncx2-/- and ncx3-/- mice showed an increased neuronal vulnerability after the ischemic insult induced by transient middle cerebral artery occlusion. As the ubiquitous deletion of NCX1 brings about to an early death of embryos because of a lack of heartbeat, this strategy could not be successfully pursued. However, information on the role of NCX1 in normal and ischemic brain could be obtained by developing conditional knockout mice lacking NCX1 in the brain. Preliminarily results obtained in these conditional mice suggest that also NCX1 protects neurons from ischemic cell death. Overall, the use of genetic-modified mice for NCX1, NCX2, and NCX3 represents a fruitful strategy to characterize the physiological role exerted by NCX in CNS and to identify the isoforms of the antiporter as potential molecular targets for therapeutic intervention in cerebral ischemia.

Original languageEnglish
Title of host publicationAdvances in Experimental Medicine and Biology
Pages213-222
Number of pages10
Volume961
DOIs
Publication statusPublished - 2013

Publication series

NameAdvances in Experimental Medicine and Biology
Volume961
ISSN (Print)00652598

Keywords

  • Brain ischemia
  • Knockout mice
  • Learning and memory
  • NCX1, NCX2, NCX3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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  • Cite this

    Molinaro, P., Cataldi, M., Cuomo, O., Viggiano, D., Pignataro, G., Sirabella, R., Secondo, A., Boscia, F., Pannaccione, A., Scorziello, A., Sokolow, S., Herchuelz, A., Di Renzo, G., & Annunziato, L. (2013). Genetically modified mice as a strategy to unravel the role played by the Na+/Ca2+ exchanger in brain ischemia and in spatial learning and memory deficits. In Advances in Experimental Medicine and Biology (Vol. 961, pp. 213-222). (Advances in Experimental Medicine and Biology; Vol. 961). https://doi.org/10.1007/978-1-4614-4756-6-18