Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition.
Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition.
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DOI：
10.1016/j.bbr.2008.12.034
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发表时间：
2009-06-08
影响因子：
2.7
通讯作者：
Dineley, Kelly T.
中科院分区：
文献类型：
--
作者：
Taglialatela, Giulio;Hogan, Dale;Zhang, Wen-Ru;Dineley, Kelly T.
关键词：
Tg2576转基因小鼠是一种广泛表征的阿尔茨海默病（AD）动物模型。与阿尔茨海默氏症类似，这些小鼠在几种形式的陈述性记忆中遭受进行性衰退，包括情境恐惧条件反射和新物体识别（NOR）。最近对这个和其他AD动物模型的研究表明，最初的认知缺陷是由于突触功能障碍，通过正确的干预，是完全可以治疗的。我们最近报道了FK506的急性钙调神经磷酸酶（CaN）抑制改善了5个月大的Tg2576的一种形式的陈述性记忆（情境恐惧条件反射）损伤。本研究通过使用NOR范式测试急性CaN抑制是否可以挽救另一种形式的陈述性记忆，即自发物体识别的缺陷。此外，我们确定FK506对NOR缺陷的拯救是否取决于所采用的保留间隔，因此是否仅限于短期、中期或长期记忆（分别为STM、ITM或LTM）。在物体识别方面，当NOR作为STM任务进行测试时，Tg2576未受到损害，并且FK506对CaN的抑制不会影响Tg2576或WT小鼠的NOR STM表现。与WT小鼠相比，分别采用4小时或24小时的保留时间来模拟ITM和LTM时，NOR中的Tg2576受损。在Tg2576小鼠中，训练前和训练期间的急性CaN抑制逆转了这些缺陷，但对WT表现没有影响。我们的研究结果表明，当使用NOR作为ITM和LTM的测试时，异常的CaN活性介导了5个月大Tg2576的物体识别缺陷。在人类阿尔茨海默病中，CaN抑制可能会导致治疗方法改善陈述性记忆的表现，正如阿尔茨海默病小鼠模型所证明的那样。
The Tg2576 transgenic mouse is an extensively characterized animal model for Alzheimer’s disease (AD). Similar to AD, these mice suffer from progressive decline in several forms of declarative memory including contextual fear conditioning and novel object recognition (NOR). Recent work on this and other AD animal models suggests that initial cognitive deficits are due to synaptic dysfunction that, with the correct intervention, are fully treatable. We recently reported that acute calcineurin (CaN) inhibition with FK506 ameliorates one form of declarative memory (contextual fear conditioning) impairment in 5 months old Tg2576. This study tested whether acute CaN inhibition rescues deficits in an additional form of declarative memory, spontaneous object recognition, by employing the NOR paradigm. Furthermore, we determined whether FK506 rescue of NOR deficits depends on the retention interval employed and therefore is restricted to short-term, intermediate-term, or long-term memory (STM, ITM or LTM, respectively). In object recognition, Tg2576 are unimpaired when NOR is tested as a STM task and CaN inhibition with FK506 does not influence NOR STM performance in Tg2576 or WT mice. Tg2576 were impaired in NOR compared to WT mice when a 4 or 24 hour retention interval was employed to model ITM and LTM, respectively. Acute CaN inhibition prior to and during the training session reversed these deficits in Tg2576 mice with no effect on WT performance. Our findings demonstrate that aberrant CaN activity mediates object recognition deficits in 5 months old Tg2576 when NOR is employed as a test for ITM and LTM. In human AD, CaN inhibition may lead the way for therapeutics to improve declarative memory performance as demonstrated in a mouse model for AD.
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