Weeber Edwin J, Jiang Yong-Hui, Elgersma Ype, Varga Andrew W, Carrasquillo Yarimar, Brown Sarah E, Christian Jill M, Mirnikjoo Banefsheh, Silva Alcino, Beaudet Arthur L, Sweatt J David
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
J Neurosci. 2003 Apr 1;23(7):2634-44. doi: 10.1523/JNEUROSCI.23-07-02634.2003.
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.
天使综合征（AS）是一种人类认知障碍，其特征为严重智力迟钝和癫痫。最近，一种AS小鼠模型（Ube3a母源无效突变）被培育出来，该模型在情境依赖学习和海马体长期增强（LTP）方面均表现出缺陷。在本研究中，我们探究了这些LTP和学习缺陷的分子基础。突变动物的海马体磷酸化钙/钙调蛋白依赖性蛋白激酶II（CaMKII）显著增加，特别是在苏氨酸（Thr）286和苏氨酸305位点，而总CaMKII水平没有相应变化。此外，突变体的CaMKII活性、自身磷酸化能力以及与突触后致密物相关的总CaMKII均降低。这些发现首次表明CaMKII调节异常是人类学习障碍中神经行为缺陷的分子原因。
