Modulation of sphingosine 1-phosphate (S1P) attenuates spatial learning and memory impairments in the valproic acid rat model of autism
Modulation of sphingosine 1-phosphate (S1P) attenuates spatial learning and memory impairments in the valproic acid rat model of autism
复制标题
1-磷酸鞘氨醇 (S1P) 的调节可减轻丙戊酸自闭症大鼠模型的空间学习和记忆障碍
DOI：
10.1007/s00213-017-4805-4
复制
发表时间：
2018-03
影响因子：
3.4
通讯作者：
Wu Lijie
中科院分区：
文献类型：
--
作者：
Wu Hongmei;Zhang Quanzhi;Gao Jingquan;Sun Caihong;Wang Jia;Xia Wei;Cao Yonggang;Hao Yanqiu;Wu Lijie
自闭症谱系障碍（ASD）是一组普遍存在于儿童早期的神经发育障碍，它正在成长为儿童残疾的主要原因。然而，ASD的病因和治疗方法尚不清楚。在我们之前的研究中，我们发现自闭症儿童血清中鞘氨醇1-磷酸（S1P）水平显著升高，提示S1P水平可能与ASD有关。目的本研究的目的是确定自闭症患者中S1P水平升高与神经行为改变之间的联系。方法采用丙戊酸（VPA）诱导的自闭症大鼠模型，观察血清和海马组织中S1P的表达水平以及S1P生成的关键酶鞘氨酸激酶（SphK）的表达。此外，我们评估了暴露于vpa的大鼠在SphK阻断后的认知功能变化、组织病理学和神经化学变化，以探索自闭症中S1P水平升高与神经行为变化之间的可能联系。结果我们发现，vpa暴露大鼠海马组织中SphK2和S1P水平上调，而药理抑制SphK可降低S1P水平，减轻空间学习和记忆障碍，增加磷酸化CaMKII、CREB和自噬相关蛋白的表达，抑制细胞色素c的释放，降低凋亡相关蛋白的表达，防止海马神经元丢失。结论SphK2/S1P表达水平升高与自闭症空间学习记忆障碍有关，这一信号通路为今后的研究提供了新的治疗靶点和方向。
RationaleAutism spectrum disorders (ASD) are a set of pervasive neurodevelopmental disorders that manifest in early childhood, and it is growing up to be a major cause of disability in children. However, the etiology and treatment of ASD are not well understood. In our previous study, we found that serum levels of sphingosine 1-phosphate (S1P) were increased significantly in children with autism, indicating that S1P levels may be involved in ASD.ObjectiveThe objective of this study was to identify a link between increased levels of S1P and neurobehavioral changes in autism.MethodsWe utilized a valproic acid (VPA) -induced rat model of autism to evaluate the levels of S1P and the expression of sphingosine kinase (SphK), a key enzyme for S1P production, in serum and hippocampal tissue. Furthermore, we assessed cognitive functional changes and histopathological and neurochemical alterations in VPA-exposed rats after SphK blockade to explore the possible link between increased levels of S1P and neurobehavioral changes in autism.ResultsWe found that SphK2 and S1P are upregulated in hippocampal tissue from VPA-exposed rats, while pharmacological inhibition of SphK reduced S1P levels, attenuated spatial learning and memory impairments, increased the expression of phosphorylated CaMKII and CREB and autophagy-related proteins, inhibited cytochrome c release, decreased the expression of apoptosis related proteins, and protected against neuronal loss in the hippocampus.ConclusionWe have demonstrated that an increased level of SphK2/S1P is involved in the spatial learning and memory impairments of autism, and this signaling pathway represents a novel therapeutic target and direction for future studies.
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影响因子：
3.3
作者：
Sivasubramanian, M.;Kanagaraj, N.;Tay, S. S. W.
通讯作者：
Tay, S. S. W.
影响因子：
5.3
作者：
Lahiri DK;Sokol DK;Erickson C;Ray B;Ho CY;Maloney B
通讯作者：
Maloney B
影响因子：
--
作者：
Benjamin Zablotsky;Lindsey I. Black;M. Maenner;L. Schieve;S. Blumberg
通讯作者：
Benjamin Zablotsky;Lindsey I. Black;M. Maenner;L. Schieve;S. Blumberg
影响因子：
1.9
作者：
Seo TB;Cho HS;Shin MS;Kim CJ;Ji ES;Baek SS
通讯作者：
Baek SS
影响因子：
16.2
作者：
Tang, Guomei;Gudsnuk, Kathryn;Kuo, Sheng-Han;Cotrina, Marisa L.;Rosoklija, Gorazd;Sosunov, Alexander;Sonders, Mark S.;Kanter, Ellen;Castagna, Candace;Yamamoto, Ai;Yue, Zhenyu;Arancio, Ottavio;Peterson, Bradley S.;Champagne, Frances;Dwork, Andrew J.;Goldman, James;Sulzer, David
通讯作者：
Sulzer, David