LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus
LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus
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DOI：
10.1523/jneurosci.6271-11.2012
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发表时间：
2012-03-21
影响因子：
5.3
通讯作者：
Chen, Hsiao-Huei
中科院分区：
文献类型：
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作者：
Qin, Zhaohong;Zhou, Xun;Chen, Hsiao-Huei
LIM domain only 4（LMO 4）转录辅因子激活神经元中的基因表达并调节网络形成的关键方面，但其机制尚不清楚。在这里，我们表明，LMO 4积极调节兰尼碱受体2型（RyR 2）的表达，从而表明LMO 4调节钙诱导的钙释放（CICR）在中枢神经元。我们发现，CICR调制CA 3神经元的前脑特异性缺失LMO 4（LMO 4 KO）的小鼠严重受损，但可以恢复单细胞过表达LMO 4。与这些发现一致，双光子钙成像实验表明，咖啡因对RyR介导的钙从内部储存中释放的增强作用在LMO 4 KO神经元中不存在。CICR对动作电位序列期间诱导的谷氨酸释放的总体促进作用在LMO 4 KO中同样有缺陷，证实了CICR机制在这些神经元中严重受损。此外，在LMO 4 KO小鼠中，CA 3-CA 1长时程增强的幅度降低，这似乎是继发于谷氨酸释放概率总体降低的缺陷。通过莫里斯水迷宫测试确定，LMO 4 KO小鼠的这些细胞表型伴有海马依赖性空间学习缺陷。因此，我们的研究结果确立了LMO 4作为中枢神经元中CICR的关键调节因子，为LMO 4调节广泛的神经元功能和行为提供了机制。
The LIM domain only 4 (LMO4) transcription cofactor activates gene expression in neurons and regulates key aspects of network formation, but the mechanisms are poorly understood. Here, we show that LMO4 positively regulates ryanodine receptor type 2 (RyR2) expression, thereby suggesting that LMO4 regulates calcium-induced calcium release (CICR) in central neurons. We found that CICR modulation of the afterhyperpolarization in CA3 neurons from mice carrying a forebrain-specific deletion of LMO4 (LMO4 KO) was severely compromised but could be restored by single-cell overexpression of LMO4. In line with these findings, two-photon calcium imaging experiments showed that the potentiation of RyR-mediated calcium release from internal stores by caffeine was absent in LMO4 KO neurons. The overall facilitatory effect of CICR on glutamate release induced during trains of action potentials was likewise defective in LMO4 KO, confirming that CICR machinery is severely compromised in these neurons. Moreover, the magnitude of CA3-CA1 long-term potentiation was reduced in LMO4 KO mice, a defect that appears to be secondary to an overall reduced glutamate release probability. These cellular phenotypes in LMO4 KO mice were accompanied with deficits in hippocampus-dependent spatial learning as determined by the Morris water maze test. Thus, our results establish LMO4 as a key regulator of CICR in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.