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首页> 外文期刊>The European Journal of Neuroscience >Metaplasticity of the late-phase of long-term potentiation: a critical role for protein kinase A in synaptic tagging.
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Metaplasticity of the late-phase of long-term potentiation: a critical role for protein kinase A in synaptic tagging.

机译：长期增强后期阶段的可塑性：蛋白激酶A在突触标记中的关键作用。

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The late-phase of long-term potentiation (L-LTP) in hippocampal area CA1 requires gene expression and de novo protein synthesis but it is expressed in an input-specific manner. The 'synaptic tag' theory proposes that gene products can only be captured and utilized at synapses that have been 'tagged' by previous activity. The mechanisms underlying synaptic tagging, and its activity dependence, are largely undefined. Previously, we reported that low-frequency stimulation (LFS) decreases the stability of L-LTP in a cell-wide manner by impairing synaptic tagging. We show here that a phosphatase inhibitor, okadaic acid, blocked homosynaptic and heterosynaptic inhibition of L-LTP by prior LFS. In addition, prior LFS homosynaptically and heterosynaptically impaired chemically induced synaptic facilitation elicited by forskolin/3-isobutyl-1-methylxanthine, suggesting that there is a cell-wide dampening of cAMP/protein kinase A (PKA) signaling concurrent with phosphatase activation. We propose that prior LFS impairs expression of L-LTP by inhibiting synaptic tagging through its actions on the cAMP/PKA pathway. In support of this notion, we show that hippocampal slices from transgenic mice that have genetically reduced hippocampal PKA activity display impaired synaptic capture of L-LTP. An inhibitor of PKA, KT-5720, also blocked synaptic capture of L-LTP. Moreover, pharmacological activation of the cAMP/PKA pathway can produce a synaptic tag to capture L-LTP expression, resulting in persistent synaptic facilitation. Collectively, our results show that PKA is critical for synaptic tagging and for input-specific L-LTP. PKA-mediated signaling can be constrained by prior episodes of synaptic activity to regulate subsequent L-LTP expression and perhaps control the integration of multiple synaptic events over time.
机译：海马区CA1中的长期增强（L-LTP）的后期需要基因表达和从头合成蛋白质，但以输入特定的方式表达。 “突触标记”理论提出基因产物只能在已被先前活动“标记”的突触中捕获和利用。突触标记的基础机制及其活动依赖性在很大程度上尚未定义。以前，我们报道了低频刺激（LFS）通过损害突触标记降低了L-LTP在整个细胞范围内的稳定性。我们在这里显示，磷酸酶抑制剂冈田酸通过先前的LFS阻断了L-LTP的同突触和异突触抑制。另外，以前的LFS通过福斯高林/ 3-异丁基-1-甲基黄嘌呤引起的同型和异型突触损伤化学诱导的突触促进作用，提示cAMP /蛋白激酶A（PKA）信号在细胞范围内受到抑制，同时磷酸酶活化。我们建议，以前的LFS通过抑制其在cAMP / PKA途径上的作用来抑制突触标记，从而损害L-LTP的表达。为了支持该观点，我们显示了转基因小鼠海马PKA活性遗传降低的海马切片显示L-LTP的突触捕获受损。 PKA的抑制剂KT-5720也可以阻止L-LTP的突触捕获。此外，cAMP / PKA途径的药理激活可以产生一个突触标签来捕获L-LTP表达，从而导致持续的突触促进作用。总的来说，我们的结果表明PKA对于突触标记和输入特定L-LTP至关重要。 PKA介导的信号传导可能受到突触活动先前发作的约束，以调节随后的L-LTP表达，并可能随时间控制多个突触事件的整合。

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