Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin
Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin
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DOI：
10.1016/s0092-8674(01)00264-1
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发表时间：
2001-03-09
期刊：
影响因子：
64.5
通讯作者：
Mansuy, IM
中科院分区：
文献类型：
--
作者：
Malleret, G;Haditsch, U;Mansuy, IM
突触可塑性和记忆储存的阈值被认为是由PKA激酶和钙调磷酸酶介导的蛋白质磷酸化和去磷酸化之间的平衡决定的。为了确定内源性钙调神经磷酸酶是否在这种平衡中起抑制性约束作用，我们研究了遗传抑制钙调神经磷酸酶对可塑性和记忆的影响。使用强力霉素依赖的rtTA系统在小鼠脑中可逆地表达钙调神经磷酸酶抑制剂，我们发现钙调神经磷酸酶活性的瞬时降低促进体外和体内的LTP。这种促进作用是PKA依赖性的，并在体内持续数天。它伴随着增强的学习和加强短期和长期记忆在几个依赖于空间和非空间任务。通过抑制转基因表达，LTP和记忆改善被完全逆转。这些结果表明，内源性钙调磷酸酶抑制LTP和记忆。
The threshold for hippocampal-dependent synaptic plasticity and memory storage is thought to be determined by the balance between protein phosphorylation and dephosphorylation mediated by the kinase PKA and the phosphatase calcineurin. To establish whether endogenous calcineurin acts as an inhibitory constraint in this balance, we examined the effect of genetically inhibiting calcineurin on plasticity and memory. Using the doxycycline-dependent rtTA system to express a calcineurin inhibitor reversibly in the mouse brain, we find that the transient reduction of calcineurin activity facilitates LTP in vitro and in vivo. This facilitation is PKA dependent and persists over several days in vivo. It is accompanied by enhanced learning and strengthened short- and long-term memory in several hippocampal-dependent spatial and nonspatial tasks. The LTP and memory improvements are reversed fully by suppression of transgene expression. These results demonstrate that endogenous calcineurin constrains LTP and memory.