Reduction in memory in passive avoidance learning, exploratory behaviour and synaptic plasticity in mice with a spontaneous deletion in the ubiquitin C-terminal hydrolase L1 gene
Reduction in memory in passive avoidance learning, exploratory behaviour and synaptic plasticity in mice with a spontaneous deletion in the ubiquitin C-terminal hydrolase L1 gene
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DOI：
10.1111/j.1460-9568.2008.06047.x
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发表时间：
2008-02-01
影响因子：
3.4
通讯作者：
Wada, Keiji
中科院分区：
文献类型：
--
作者：
Sakurai, Mikako;Sekiguchi, Masayuki;Wada, Keiji
小鼠中泛素C末端水解酶L1（UCH-L1）的过表达可挽救淀粉样β蛋白诱导的突触可塑性和记忆力下降然而，UCH-L1在大脑中的生理作用尚未完全了解。在本研究中，我们研究了UCH-L1在大脑中的作用，利用薄轴索营养不良（gad）小鼠与自发缺失的基因Uch-L1作为功能丧失的模型。尽管gad小鼠在12周龄时就开始表现出运动性轻瘫，但在没有明显运动性轻瘫的更小年龄时分析它们的大脑表型是可能的。在6周龄gad小鼠中，被动回避测试中的记忆维持和旷场测试中的探索行为减少。θ-爆发刺激诱导的长时程增强（LTP）的场突触反应从Schaffer侧支到海马脑片CA1区锥体细胞的维持也受损gad小鼠。gad小鼠的LTP对放线菌素D不敏感，表明LTP的转录依赖性成分受损。磷酸化的环磷酸腺苷反应元件结合蛋白（CREB）在CA1区的海马切片从gad小鼠发生早于野生型小鼠的切片，是短暂的，这表明CREB磷酸化在gad小鼠改变。这些结果表明，gad小鼠的被动回避学习记忆、探索行为和海马CA1 LTP降低。我们认为UCH-L1介导的CREB磷酸化的时间完整性和持久性的维持是这些损伤的基础。
Overexpression of ubiquitin C-terminal hydrolase L1 (UCH-L1) in mice rescues amyloid beta-protein-induced decreases in synaptic plasticity and memory. However, the physiological role of UCH-L1 in the brain is not fully understood. In the present study, we investigated the role of UCH-L1 in the brain by utilizing gracile axonal dystrophy (gad) mice with a spontaneous deletion in the gene Uch-l1 as a loss-of-function model. Although gad mice exhibit motor paresis beginning at similar to 12 weeks of age, it is possible to analyse their brain phenotypes at a younger age when no motor paresis is evident. Maintenance of memory in a passive avoidance test and exploratory behaviour in an open field test were reduced in 6-week-old gad mice. The maintenance of theta-burst stimulation-induced long-term potentiation (LTP) of field synaptic responses from Schaffer collaterals to CA1 pyramidal cells in hippocampal slices was also impaired in gad mice. The LTP in gad mice was insensitive to actinomycin D, suggesting that a transcription-dependent component of the LTP is impaired. Phosphorylation of cyclic AMP response element binding protein (CREB) in the CA1 region of hippocampal slices from gad mice occurred earlier than in the slices from wild-type mice and was transient, suggesting that CREB phosphorylation is altered in gad mice. These results suggest that memory in passive avoidance learning, exploratory behaviour and hippocampal CA1 LTP are reduced in gad mice. We propose that UCH-L1-mediated maintenance of the temporal integrity and persistence of CREB phosphorylation underlies these impairments.