Department of Pediatrics, Division of Pediatric Neurology, New York Presbyterian Hospital, Laboratory of Molecular and Developmental Neurobiology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Behav Brain Res. 2012 Jan 15;226(2):428-34. doi: 10.1016/j.bbr.2011.09.039. Epub 2011 Oct 4.
A nonsense mutation in the human cereblon gene (CRBN) causes a mild type of autosomal recessive non-syndromic intellectual disability (ID). Animal studies show that crbn is a cytosolic protein with abundant expression in the hippocampus (HPC) and neocortex (CTX). Its diverse functions include the developmental regulation of ion channels at the neuronal synapse, the mediation of developmental programs by ubiquitination, and a target for herpes simplex type I virus in HPC neurons. To test the hypothesis that anomalous CRBN expression leads to HPC-mediated memory and learning deficits, we generated germ-line crbn knock-out mice (crbn(-/-)). We also inactivated crbn in forebrain neurons in conditional knock-out mice in which crbn exons 3 and 4 are deleted by cre recombinase under the direction of the Ca(2+)/calmodulin-dependent protein kinase II alpha promoter (CamKII(cre/+), crbn(-/-)). crbn mRNA levels were negligible in the HPC, CTX, and cerebellum (CRBM) of the crbn(-/-) mice. In contrast, crbn mRNA levels were reduced 3- to 4-fold in the HPC, CTX but not in the CRBM in CamKII(cre/+), crbn(-/-) mice as compared to wild type (CamKII(cre/+), crbn(+/+)). Contextual fear conditioning showed a significant decrease in the percentage of freezing time in CamKII(cre/+), crbn(-/-) and crbn(-/-) mice while motor function, exploratory motivation, and anxiety-related behaviors were normal. These findings suggest that CamKII(cre/+), crbn(-/-) mice exhibit selective HPC-dependent deficits in associative learning and supports the use of these mice as in vivo models to study the functional consequences of CRBN aberrations on memory and learning in humans.
人类 cereblon 基因（CRBN）中的无意义突变导致一种轻度的常染色体隐性非综合征性智力障碍（ID）。动物研究表明，CRBN 是一种胞质蛋白，在海马体（HPC）和新皮层（CTX）中大量表达。其多种功能包括神经元突触处离子通道的发育调节、泛素化介导的发育程序以及 HPC 神经元中单纯疱疹 I 型病毒的靶标。为了验证异常 CRBN 表达导致 HPC 介导的记忆和学习缺陷的假设，我们生成了生殖系 crbn 敲除小鼠（crbn(-/-)）。我们还在条件性敲除小鼠中使 forebrain 神经元中的 crbn 失活，其中 crbn 外显子 3 和 4 通过 cre 重组酶在 Ca(2+)/钙调蛋白依赖性蛋白激酶 II alpha 启动子（CamKII(cre/+), crbn(-/-)）的指导下缺失。crbn(-/-) 小鼠的 HPC、CTX 和小脑（CRBM）中 crbn mRNA 水平可忽略不计。相比之下，CamKII(cre/+), crbn(-/-) 小鼠的 HPC、CTX 中 crbn mRNA 水平降低了 3-4 倍，但 CRBM 中 crbn mRNA 水平没有降低，与野生型（CamKII(cre/+), crbn(+/+)）相比。情景性恐惧条件反射显示，CamKII(cre/+), crbn(-/-) 和 crbn(-/-) 小鼠的冻结时间百分比显着下降，而运动功能、探索性动机和焦虑相关行为正常。这些发现表明，CamKII(cre/+), crbn(-/-) 小鼠表现出与海马体依赖性相关的学习和记忆缺陷，支持使用这些小鼠作为体内模型来研究 CRBN 异常对人类记忆和学习的功能后果。
