Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome.
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.
Weeber
Edwin J
EJ
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Jiang
Yong-Hui
YH
Elgersma
Ype
Y
Varga
Andrew W
AW
Carrasquillo
Yarimar
Y
Brown
Sarah E
SE
Christian
Jill M
JM
Mirnikjoo
Banefsheh
B
Silva
Alcino
A
Beaudet
Arthur L
AL
Sweatt
J David
JD
D017204:Angelman Syndrome / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D006624:Hippocampus / Q000201:enzymology* / Q000502:physiology; D007150:Immunohistochemistry; D008607:Intellectual Disability / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D008025:Ligases / Q000235:genetics; D017774:Long-Term Potentiation; D051379:Mice; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D013569:Synapses / Q000201:enzymology; D013912:Threonine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D013912:Threonine; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D008025:Ligases