Increased Activity of Src Homology 2 Domain Containing Phosphotyrosine Phosphatase 2 (Shp2) Regulates Activity-dependent AMPA Receptor Trafficking
Increased Activity of Src Homology 2 Domain Containing Phosphotyrosine Phosphatase 2 (Shp2) Regulates Activity-dependent AMPA Receptor Trafficking
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含有磷酸酪氨酸磷酸酶 2 (Shp2) 的 Src 同源 2 结构域活性增加调节活性依赖性 AMPA 受体贩运
DOI：
10.1074/jbc.m116.714501
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发表时间：
2016-09-02
影响因子：
4.8
通讯作者：
Luo, Jian-hong
中科院分区：
文献类型：
--
作者：
Zhang, Bin;Du, Yong-lan;Luo, Jian-hong
长期突触可塑性，如长期增强（LTP），已被广泛认为是一种潜在记忆的细胞机制。最近，人们发现Shp2在果蝇和小鼠的突触可塑性和记忆中发挥作用，揭示了Shp2在认知功能中的显著和保守作用。然而，Shp2在突触可塑性和记忆中的确切机制仍不清楚。在这里，我们研究了Shp2在海马LTP和情境性撕裂调节中的调节作用。我们发现，在LTP诱导后，Shp2被迅速招募到脊髓中。此外，在培养的海马神经元或急性切片中，LTP刺激后，tyr542处Shp2磷酸化水平升高。值得注意的是，情境恐惧条件反射也调节了Shp2在tyr1 -542位点的磷酸化水平，表明Shp2在LTP和记忆形成过程中有精细调节。通过在培养的神经元中使用Shp2特异性抑制剂和腺相关病毒cre介导的Shp2敲除，我们提供了证据，证明Shp2的磷酸酶活性对于活性依赖的AMPA受体表面运输至关重要。总之，我们的研究结果揭示了Shp2在LTP和记忆中的调节机制，拓宽了我们对Shp2在认知功能中的理解。
Long term synaptic plasticity, such as long term potentiation (LTP), has been widely accepted as a cellular mechanism underlying memory. Recently, it has been unraveled that Shp2 plays a role in synaptic plasticity and memory in Drosophila and mice, revealing significant and conserved effects of Shp2 in cognitive function. However, the exact mechanism underlying this function of Shp2 in synaptic plasticity and memory still remains elusive. Here, we examine the regulation of Shp2 in hippocampal LTP and contextual tear conditioning. We find that Shp2 is rapidly recruited into spines after LTP induction. Furthermore, the phosphorylation level of Shp2 at Tyr-542 is elevated after LTP stimuli either in cultured hippocampal neurons or acute slices. Notably, contextual fear conditioning also regulates the phosphorylation level of Shp2 at Tyr-542, suggesting fine-tuned regulation of Shp2 in LTP and memory formation. By using a Shp2-specific inhibitor and adeno-associated virus-Cre mediated Shp2 knock-out in cultured neurons, we provide evidence that the phosphatase activity of Shp2 is critical for activity-dependent AMPA receptor surface trafficking. Collectively, our results have revealed a regulatory mechanism of Shp2 underlying LTP and memory, broadening our understanding of Shp2 in cognitive function.