Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice:: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration
Chromatin acetylation, memory, and LTP are impaired in CBP+/- mice:: A model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration
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DOI：
10.1016/j.neuron.2004.05.021
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发表时间：
2004-06-24
期刊：
影响因子：
16.2
通讯作者：
Barco, A
中科院分区：
文献类型：
--
作者：
Alarcón, JM;Malleret, G;Barco, A
我们研究了Rubinstein-Taybi综合征（RTS）的单倍不足形式的小鼠模型，RTS是一种由CREB结合蛋白（CBP）编码基因突变引起的遗传性疾病，其特征是精神发育迟滞和骨骼异常。在这些小鼠中，染色质乙酰化，某些形式的长期记忆和海马长时程增强（L-LTP）的晚期相受损。我们以两种方式改善L-LTP缺陷：（1）通过增强CREB依赖性基因的表达，以及（2）通过抑制组蛋白脱乙酰基转移酶活性（HDAC），CBP的组蛋白乙酰化功能的分子对应物。抑制HDAC也逆转了恐惧条件反射中观察到的记忆缺陷。这些研究结果表明，RTS上观察到的一些认知和生理缺陷不仅仅是由于发育期间CBP的减少，也可能是由于CREB共激活和CBP的组蛋白乙酰化功能在整个生命过程中的持续需求。
We studied a mouse model of the haploinsufficiency form of Rubinstein-Taybi syndrome (RTS), an inheritable disorder caused by mutations in the gene encoding the CREB binding protein (CBP) and characterized by mental retardation and skeletal abnormalities. In these mice, chromatin acetylation, some forms of long-term memory, and the late phase of hippocampal long-term potentiation (L-LTP) were impaired. We ameliorated the L-LTP deficit in two ways: (1) by enhancing the expression of CREB-dependent genes, and (2) by inhibiting histone deacetyltransferase activity (HDAC), the molecular counterpart of the histone acetylation function of CBP. Inhibition of HDAC also reversed the memory defect observed in fear conditioning. These findings suggest that some of the cognitive and physiological deficits observed on RTS are not simply due to the reduction of CBP during development but may also result from the continued requirement throughout life for both the CREB co-activation and the histone acetylation function of CBP.