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The Journal of Neuroscience, November 28, 2007, 27(48):13161-13172; doi:10.1523/JNEUROSCI.3974-07.2007

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Neurobiology of Disease
The Down Syndrome Critical Region Protein RCAN1 Regulates Long-Term Potentiation and Memory via Inhibition of Phosphatase Signaling

Charles A. Hoeffer,^1,6 Asim Dey,³ Nita Sachan,³ Helen Wong,⁶ Richard J. Patterson,¹ John M. Shelton,³ James A. Richardson,^4,5 Eric Klann,^1,2,6 and Beverly A. Rothermel³

Departments of ¹Molecular Physiology and Biophysics and ²Neuroscience, Baylor College of Medicine, Houston, Texas 77030, Departments of ³Internal Medicine, ⁴Molecular Biology, and ⁵Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ⁶Center for Neural Science, New York University, New York, New York 10003

Correspondence should be addressed to Eric Klann, Center for Neural Science, 4 Washington Place, Room 809, New York University, New York, NY 10003. Email: eklann{at}cns.nyu.edu

Regulator of calcineurin 1 (RCAN1/MCIP1/DSCR1) regulates the calmodulin-dependent phosphatase calcineurin. Because it is located on human chromosome 21, RCAN1 has been postulated to contribute to mental retardation in Down syndrome and has been reported to be associated with neuronal degeneration in Alzheimer's disease. The studies herein are the first to assess the role of RCAN1 in memory and synaptic plasticity by examining the behavioral and electrophysiological properties of RCAN1 knock-out mice. These mice exhibit deficits in spatial learning and memory, reduced associative cued memory, and impaired late-phase long-term potentiation (L-LTP), phenotypes similar to those of transgenic mice with increased calcineurin activity. Consistent with this, the RCAN1 knock-out mice display increased enzymatic calcineurin activity, increased abundance of a cleaved calcineurin fragment, and decreased phosphorylation of the calcineurin substrate dopamine and cAMP-regulated phosphoprotein-32. We propose a model in which RCAN1 plays a positive role in L-LTP and memory by constraining phosphatase signaling.

Key words: calcineurin; protein phosphatase; mental retardation; hippocampus; learning and memory; synaptic plasticity

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Received March 13, 2007; revised Oct. 9, 2007; accepted Oct. 16, 2007.

Correspondence should be addressed to Eric Klann, Center for Neural Science, 4 Washington Place, Room 809, New York University, New York, NY 10003. Email: eklann{at}cns.nyu.edu

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