Lei Mona, Shafique Adeena, Shang Kani, Couttas Timothy A, Zhao Hua, Don Anthony S, Karl Tim
Prince of Wales Clinical School, University of New South Wales, NSW 2052, Australia; Centenary Institute and Sydney Medical School, University of Sydney, NSW 2006, Australia.
Prince of Wales Clinical School, University of New South Wales, NSW 2052, Australia.
Behav Brain Res. 2017 Aug 30;333:9-16. doi: 10.1016/j.bbr.2017.06.019. Epub 2017 Jun 15.
The lipid sphingosine 1-phosphate (S1P) is a potent neuroprotective signalling molecule that signals through its own family of five G-protein coupled receptors. S1P signalling enhances presynaptic glutamate release and is essential for neural development. S1P is synthesized by the enzymes sphingosine kinases 1 and 2 (SPHK1 and SPHK2), of which SPHK2 mRNA and activity is more abundant in the brain. In this study we investigated the consequences of global SphK2 knockout (SphK2) on basic motor capabilities, anxiety, learning, and memory in mice, using a range of tests including the elevated plus maze, the cheeseboard, contextual and cued fear conditioning, and fear extinction. Loss of SphK2 resulted in an 85-90% reduction in brain S1P levels, and was associated with a notably higher freezing response in a novel context. SphK2 knockout mice also exhibited increased contextual fear conditioning but the extinction of contextual fear memory was similar to control mice. SphK2 mice, contrary to their control littermates, did not respond to cue presentation with increased freezing. Anxiety measures in the elevated plus maze were not different between SphK2 mice and control littermates. Also, knockout mice showed no deficits in neurological reflexes or motor functions, and performed as well as their control littermates in the spatial memory test. Our findings demonstrate that SphK2 is responsible for the vast majority of S1P synthesis in the mouse brain, and plays a role in freezing responses as evaluated in the fear conditioning paradigm.
脂质鞘氨醇 1 - 磷酸（S1P）是一种强效的神经保护信号分子，它通过自身的五个 G 蛋白偶联受体家族进行信号传导。S1P 信号传导增强突触前谷氨酸释放，对神经发育至关重要。S1P 由鞘氨醇激酶 1 和 2（SPHK1 和 SPHK2）合成，其中 SPHK2 mRNA 和活性在大脑中更为丰富。在本研究中，我们使用一系列测试，包括高架十字迷宫、棋盘试验、情境性和线索性恐惧条件反射以及恐惧消退试验，研究了全局 SphK2 基因敲除（SphK2 -/-）对小鼠基本运动能力、焦虑、学习和记忆的影响。SphK2 的缺失导致脑内 S1P 水平降低 85 - 90%，并与在新环境中显著更高的僵住反应相关。SphK2 基因敲除小鼠还表现出情境性恐惧条件反射增加，但情境性恐惧记忆的消退与对照小鼠相似。与同窝对照小鼠相反，SphK2 -/-小鼠对线索呈现没有以增加僵住反应来应答。在高架十字迷宫中的焦虑测量结果在 SphK2 -/-小鼠和同窝对照小鼠之间没有差异。此外，基因敲除小鼠在神经反射或运动功能方面没有缺陷，并且在空间记忆测试中的表现与同窝对照小鼠一样好。我们的研究结果表明，SphK2 负责小鼠大脑中绝大部分的 S1P 合成，并在恐惧条件反射范式评估的僵住反应中发挥作用。
