The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility.
The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility.
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DOI：
10.1016/j.neuron.2018.05.012
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发表时间：
2018-06-27
期刊：
影响因子：
16.2
通讯作者：
Corrêa SAL
中科院分区：
文献类型：
--
作者：
Wall MJ;Collins DR;Chery SL;Allen ZD;Pastuzyn ED;George AJ;Nikolova VD;Moy SS;Philpot BD;Shepherd JD;Müller J;Ehlers MD;Mabb AM;Corrêa SAL
神经元活动调节直接早期基因Arc/Arg3.1的转录和翻译，这是突触可塑性的关键介质。蛋白酶体依赖性降解严格限制了Arc的时间表达，但这种调节的意义尚不清楚。我们通过创建Arc敲入小鼠（ArcKR）来破坏Arc降解的时间控制，其中主要的Arc泛素化位点发生突变。ArcKR小鼠具有完整的空间学习能力，但在逆向学习中表现出选择最佳策略的特殊缺陷。这种认知不灵活性与Arc mRNA和蛋白表达的变化相结合，导致诱导mGluR-LTD的阈值降低和mGluR-LTD振幅增强。这些发现表明，Arc蛋白的异常持续性限制了Arc信号通路的动态范围，特别是在逆转学习过程中。我们的工作阐明了活动依赖分子（如Arc）的精确时间控制如何调节突触可塑性，并对认知至关重要。Arc泛素化位点的突变减缓了Arc的降解，Arc敲进小鼠的mGluR-LTD增强，Arc的持续存在降低了认知灵活性，Arc的泛素依赖性蛋白酶体降解严格限制了其时间表达，但这种调节的意义尚不清楚。我们制造了一只破坏电弧去除时间控制（ArcKR）的小鼠。ArcKR小鼠表现出增强的mGluR-LTD，认知灵活性受损。
Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition. Mutation of Arc ubiquitination sites slows Arc degradation Arc knockin mice have enhanced mGluR-LTD The persistence of Arc reduces cognitive flexibility Ubiquitin-dependent proteasomal degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We generated a mouse disrupting the temporal control of Arc removal (ArcKR). ArcKR mice exhibit enhanced mGluR-LTD and have impaired cognitive flexibility.
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影响因子：
3.4
作者：
DaSilva LL;Wall MJ;P de Almeida L;Wauters SC;Januário YC;Müller J;Corrêa SA
通讯作者：
Corrêa SA
影响因子：
15.9
作者：
Korb E;Finkbeiner S
通讯作者：
Finkbeiner S
影响因子：
64.5
作者：
Ashley J;Cordy B;Lucia D;Fradkin LG;Budnik V;Thomson T
通讯作者：
Thomson T
影响因子：
2.5
作者：
Auerbach, Benjamin D.;Bear, Mark F.
通讯作者：
Bear, Mark F.
影响因子：
16.2
作者：
Plath, Niels;Ohana, Ora;Kuhl, Dietmar
通讯作者：
Kuhl, Dietmar