HIPPOCAMPAL LONG-TERM DEPRESSION AND DEPOTENTIATION ARE DEFECTIVE IN MICE CARRYING A TARGETED DISRUPTION OF THE GENE ENCODING THE RI-BETA SUBUNIT OF CAMP-DEPENDENT PROTEIN-KINASE
HIPPOCAMPAL LONG-TERM DEPRESSION AND DEPOTENTIATION ARE DEFECTIVE IN MICE CARRYING A TARGETED DISRUPTION OF THE GENE ENCODING THE RI-BETA SUBUNIT OF CAMP-DEPENDENT PROTEIN-KINASE
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DOI：
10.1073/pnas.92.19.8851
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发表时间：
1995-09-12
影响因子：
11.1
通讯作者：
IDZERDA, RL
中科院分区：
文献类型：
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作者：
BRANDON, EP;ZHUO, M;IDZERDA, RL
cAMP 依赖性蛋白激酶 (PKA) 已被证明在海马长时程增强 (LTP) 中发挥重要作用，但人们对 PKA 在长期抑郁 (LTD) 中的功能知之甚少。我们结合了药理学和遗传学方法来证明 PKA 活性是同突触 LTD 和去潜能所必需的，并且 I 型调节亚基 (RI beta) 的特定神经元亚型是必需的。通过在胚胎干细胞中使用基因靶向，建立了编码 RI beta 的基因中携带无效突变的小鼠。突变小鼠的海马切片显示 LTD 严重缺陷，并且 Schaffer 侧支 -CA1 突触处的去电位丧失。这种缺陷在 RI beta 突变小鼠的外侧穿通路径齿状颗粒细胞突触处也很明显。尽管相关 RI α 蛋白代偿性增加，并且总 PKA 活性缺乏可检测到的变化，但这些小鼠的海马功能并未发生变化。 获救，表明 RI beta 具有独特的作用。由于 CA1 LTP 的后期也需要 PKA，但在 RI beta 突变小鼠中是正常的，因此我们的数据进一步表明，不同形式的突触可塑性可能采用不同的调节和催化亚基组合。
The cAMP-dependent protein kinase (PKA) has been shown to play an important role in long-term potentiation (LTP) in the hippocampus, but little is known about the function of PKA in long-term depression (LTD). We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential, Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells. Hippocampal slices from mutant mice show a severe deficit in LTD and depotentiation at the Schaffer collateral-CA1 synapse, This defect is also evident at the lateral perforant path-dentate granule cell synapse in RI beta mutant mice, Despite a compensatory increase in the related RI alpha protein and a lack of detectable changes in total PKA activity, the hippocampal function in these mice is not rescued, suggesting a unique role for RI beta. Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits.