Editors' ChoiceLearning and Memory

Smarter Mice Through Calcineurin Inhibition?

Science's STKE  20 Mar 2001:
Vol. 2001, Issue 74, pp. tw1
DOI: 10.1126/stke.2001.74.tw1

Long-term potentiation (LTP) is a form of synaptic plasticity thought to underlie processes of learning and memory in the brain. A number of kinases and phosphatases mediate signals in cells undergoing LTP; phosphorylation generally promotes LTP, whereas phosphatase activation and consequent protein dephosphorylation appear to inhibit synaptic plasticity and memory storage. Although results with knockout animals have been generally consistent with this scheme, the possibility of developmental effects or other permanent changes in synaptic function have limited the strength of the conclusions that could be drawn. To avoid these caveats and to test the role of the phosphatase calcineurin (CN) in learning, memory, and LTP, Malleret et al. generated transgenic mice in which regional and temporal control of CN activity was controlled by a reverse tetracycline-controlled transactivator system. Acute expression of an autoinhibitory domain of CN, which inhibited CN activity by about 40%, facilitated LTP in brain slices in vitro and in vivo. Furthermore, inhibition of CN enhanced short-term and long-term memory in behavioral assays, and it is noteworthy that these effects were reversible when expression of the inhibitor was terminated. The authors thus propose CN as a potential therapeutic target in treatment of memory loss or learning disorders.

G. Malleret, U. Haditsch, D. Genoux, M. W. Jones, T. V. P. Bliss, A. M. Vanhoose, C. Weitlauf, E. R. Kandel, D. G. Winder, I. M. Mansuy, Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104, 675-686 (2001). [Online Journal]