The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish.
The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish.
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DOI：
10.1371/journal.pone.0190897
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Clark KJ
中科院分区：
文献类型：
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作者：
Krug RG 2nd;Lee HB;El Khoury LY;Sigafoos AN;Petersen MO;Clark KJ
协调对压力的适当生理和行为反应的能力对生存很重要，并且在神经精神疾病中经常功能失调，这是全球残疾负担的主要原因。大量研究表明，内源性大麻素神经递质系统能够调节应激反应，并可作为这些疾病管理的治疗靶点。我们使用定量逆转录-聚合酶链反应表明，编码合成酶（abhd4, gde1, napepld），降解酶（faah, faah2a, faah2b）和结合内源性大麻素（cnr1, cnr2， gpr55样）受体的基因在斑马鱼中表达（Danio rerio）。这些基因在包括人类在内的许多其他脊椎动物中都是保守的，但脂肪酸酰胺水解酶2在小鼠和大鼠中已经丢失。我们设计了转录激活子样效应核酸酶，创造了cnr1和faah2a突变的斑马鱼，以测试这些基因在调节应激相关行为中的作用。我们发现cnr1的破坏增强了运动对高渗应激的反应。对压力的反应增加与啮齿动物文献一致，并有助于验证斑马鱼在该领域的应用。此外，我们首次发现faah2a的破坏减弱了高渗应激下的运动反应。这一后来的发现表明FAAH2可能是非啮齿动物应激反应的重要介质。因此，FAAH和FAAH2调节剂可以为应激加重性疾病提供不同的治疗选择。
The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld), enzymes that degrade (faah, faah2a, faah2b), and receptors that bind (cnr1, cnr2, gpr55-like) endocannabinoids are expressed in zebrafish (Danio rerio). These genes are conserved in many other vertebrates, including humans, but fatty acid amide hydrolase 2 has been lost in mice and rats. We engineered transcription activator-like effector nucleases to create zebrafish with mutations in cnr1 and faah2a to test the role of these genes in modulating stress-associated behavior. We showed that disruption of cnr1 potentiated locomotor responses to hyperosmotic stress. The increased response to stress was consistent with rodent literature and served to validate the use of zebrafish in this field. Moreover, we showed for the first time that disruption of faah2a attenuated the locomotor responses to hyperosmotic stress. This later finding suggests that FAAH2 may be an important mediator of stress responses in non-rodent vertebrates. Accordingly, FAAH and FAAH2 modulators could provide distinct therapeutic options for stress-aggravated disorders.
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影响因子：
3.3
作者：
Hill, M. N.;Tasker, J. G.
通讯作者：
Tasker, J. G.
影响因子：
5.3
作者：
Klee EW;Schneider H;Clark KJ;Cousin MA;Ebbert JO;Hooten WM;Karpyak VM;Warner DO;Ekker SC
通讯作者：
Ekker SC
影响因子：
4.5
作者：
Connors, Kristin A.;Valenti, Theodore W.;Lawless, Kelly;Sackerman, James;Onaivi, Emmanuel S.;Brooks, Bryan W.;Gould, Georgianna G.
通讯作者：
Gould, Georgianna G.
影响因子：
14.9
作者：
Howe DG;Bradford YM;Conlin T;Eagle AE;Fashena D;Frazer K;Knight J;Mani P;Martin R;Moxon SA;Paddock H;Pich C;Ramachandran S;Ruef BJ;Ruzicka L;Schaper K;Shao X;Singer A;Sprunger B;Van Slyke CE;Westerfield M
通讯作者：
Westerfield M
影响因子：
64.8
作者：
通讯作者：
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