Emotional memory is a rapidly acquired and persistent form of memory, and its robustness is in part determined by the initial strength of the memory. Here, we provide new evidence that the protein phosphatase calcineurin (CaN), a potent negative regulator of neuronal signaling that is known to constrain learning and memory, critically regulates the establishment of emotional memory through mechanisms involving the immediate early gene Zif268 (also known as Egr1). We found that CaN is inhibited in the amygdala during the establishment of aversive memory, but Zif268 is activated. Using inducible transgenesis in mice, we further saw that CaN inhibition and Zif268 overexpression during memory establishment strengthen the memory trace and enhance its resistance to extinction. We found that CaN inhibition correlates with increased Zif268 expression and that a common pool of proteins is regulated in the amygdala after CaN inhibition and Zif268 overexpression. Together, these findings reveal a previously unknown mechanism for the control of emotional memory that depends on CaN and Zif268.
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We thank H. Russig, F. Helmchen and B. Kampa for advice with statistical analyses, T. Bliss, S. Laroche and D. Kuhl for discussion, P. Gehrig for mass spectrometry analysis, U. Haditsch and L. Spassova for technical help, T. Rülicke and P. Pelzar for egg microinjection, G. Fischer for help with animal maintenance, and R. Schöb for graphical assistance. Mouse Zif268 cDNA was generously provided by T. Bliss (NMRC, London, UK) and the pBL-G vector by H. Bujard (ZMBH, Heidelberg, Germany). This project was funded by the University of Zürich, the Swiss Federal Institute of Technology, the National Center of Competence in Research “Neural Plasticity and Repair”, the Swiss National Science Foundation, the Human Frontier Science Program, the Slack-Gyr Foundation and the EMBO Young Investigator Program.
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