GENETIC DISRUPTION OF THE ALTERNATIVE SPLICING OF DREBRIN GENE IMPAIRS CONTEXT-DEPENDENT FEAR LEARNING IN ADULTHOOD
GENETIC DISRUPTION OF THE ALTERNATIVE SPLICING OF DREBRIN GENE IMPAIRS CONTEXT-DEPENDENT FEAR LEARNING IN ADULTHOOD
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DOI：
10.1016/j.neuroscience.2009.10.016
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发表时间：
2010-01-13
期刊：
影响因子：
3.3
通讯作者：
Shirao, T.
中科院分区：
文献类型：
--
作者：
Kojima, N.;Hanamura, K.;Shirao, T.
树突棘是兴奋性突触的突触后结构，在突触传递和可塑性中发挥重要作用。树突棘的形态和功能由基于肌动蛋白的细胞骨架网络调节。 Drebrin A 是 Drebrin 的成熟形式，是树突棘中的一种肌动蛋白结合蛋白，据称其减少与阿尔茨海默氏病的突触功能障碍有关。 drebrin E（drebrin 的一种胚胎形式）快速转化为 Drebrin A，与突触成熟同时发生。为了了解drebrin亚型转化在体内的生理作用，我们生成了基因敲除小鼠，其中drebrin A特异性外显子从drebrin基因中删除。 Drebrin A 特异性敲除 (DAKO) 小鼠表达 drebrin E，它取代了 drebrin A。亚细胞分离实验表明，DAKO 小鼠大脑中细胞质形式的 drebrin 增加。此外，DAKO 小鼠突触体中的 Drebrin 积累量远高于野生型 (WT) 小鼠。 DAKO 小鼠存活，其大脑总体形态和一般行为没有表现出明显异常。然而，DAKO 小鼠在恐惧调节后的情境依赖性冻结中受到损害。这些数据表明drebrin A在产生恐惧学习和记忆的某些过程中起着不可或缺的作用。 (C) 2010 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
Dendritic spines are postsynaptic structures at excitatory synapses that play important roles in synaptic transmission and plasticity. Dendritic spine morphology and function are regulated by an actin-based cytoskeletal network. Drebrin A, an adult form of drebrin, is an actin-binding protein in dendritic spines, and its decrease is purportedly concerned with synaptic dysfunction in Alzheimer's disease. Rapid conversion of drebrin E, an embryonic form of drebrin, to drebrin A occurs in parallel with synaptic maturation. To understand the physiological role of drebrin isoform conversion in vivo, we generated knockout mice in which a drebrin A-specific exon was deleted from the drebrin gene. Drebrin A-specific knockout (DAKO) mice expressed drebrin E, which substituted for drebrin A. Subcellular fractionation experiment indicated that cytosolic form of drebrin was increased in the brains of DAKO mice. Furthermore, drebrin accumulation in synaptosomes of DAKO mice was much higher than that of wild-type (WT) mice. DAKO mice were viable and showed no apparent abnormalities in their gross brain morphology and general behaviors. However, DAKO mice were impaired in a context-dependent freezing after fear conditioning. These data indicate that drebrin A plays an indispensable role in some processes of generating fear learning and memory. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.