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The Journal of Neuroscience, April 1, 2003, 23(7):2634

Derangements of Hippocampal Calcium/Calmodulin-Dependent Protein Kinase II in a Mouse Model for Angelman Mental Retardation Syndrome

Edwin J. Weeber¹, Yong-Hui Jiang², Ype Elgersma^{3, 4}, Andrew W. Varga¹, Yarimar Carrasquillo¹, Sarah E. Brown¹, Jill M. Christian¹, Banefsheh Mirnikjoo¹, Alcino Silva³, Arthur L. Beaudet², and J. David Sweatt¹

¹ Division of Neuroscience and ² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, ³ Department of Neurobiology, University of California, Los Angeles, Medical Center, Los Angeles, California 90095-1763, and ⁴ Department of Neuroscience, Erasmus University Rotterdam, 3000 DR Rotterdam, The Netherlands

Angelman syndrome (AS) is a disorder of human cognition characterized by severe mental retardation and epilepsy. Recently, a mouse model for AS (Ube3a maternal null mutation) was developed that displays deficits in both context-dependent learning and hippocampal long-term potentiation (LTP). In the present studies, we examined the molecular basis for these LTP and learning deficits. Mutant animals exhibited a significant increase in hippocampal phospho-calcium/calmodulin-dependent protein kinase II (CaMKII), specifically at sites Thr²⁸⁶ and Thr³⁰⁵, with no corresponding change in the levels of total CaMKII. In addition, mutants show a reduction in CaMKII activity, autophosphorylation capability, and total CaMKII associated with postsynaptic density. These findings are the first to implicate misregulation of CaMKII as a molecular cause for the neurobehavioral deficits in a human learning disorder.

Key words: Angelman syndrome; calcium/calmodulin-dependent protein kinase II; long-term potentiation; postsynaptic density; protein phosphatase; autophosphorylation

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2372634-11$05.00/0

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