Abstract
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 Thr(286) and Thr(305), 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angelman Syndrome / enzymology*
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Angelman Syndrome / etiology
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Angelman Syndrome / physiopathology
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / chemistry
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Calcium-Calmodulin-Dependent Protein Kinases / immunology
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cells, Cultured
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Hippocampus / enzymology*
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Hippocampus / physiology
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Immunohistochemistry
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Intellectual Disability / enzymology*
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Intellectual Disability / etiology
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Intellectual Disability / physiopathology
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Ligases / genetics
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Long-Term Potentiation
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Mice
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Mutation
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation
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Protein Kinases / metabolism
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Synapses / enzymology
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Threonine / metabolism
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Ubiquitin-Protein Ligases
Substances
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Threonine
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UBE3A protein, human
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Ubiquitin-Protein Ligases
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Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Phosphoprotein Phosphatases
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Ligases