Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior.
Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior.
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DOI：
10.3389/fnbeh.2015.00070
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发表时间：
2015
影响因子：
3
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Huang F;Wang T;Lan Y;Yang L;Pan W;Zhu Y;Lv B;Wei Y;Shi H;Wu H;Zhang B;Wang J;Duan X;Hu Z;Wu X
Farnesoid X受体（FXR）是一种参与胆汁酸合成和体内平衡的核激素受体。FXR功能障碍与胆汁淤积和动脉粥样硬化有关。FXR普遍存在于肝脏、胆囊和肠道，但尚不清楚它是否调节神经行为。在当前的研究中，我们验证了小鼠FXR缺陷影响特定神经递质子集并导致独特行为表型的假设。FXR基因敲除小鼠表现出较少的抑郁样和焦虑相关行为，但运动活动增加。他们记忆力受损，运动协调能力下降。海马和小脑的谷氨酸能、gaba能、血清素能和去甲肾上腺素能神经传递均有变化。FXR缺失降低了海马GABA合成酶GAD65的量，但增加了大脑皮层GABA转运体GAT1的量。FXR缺失增加了许多胆汁酸的血清浓度，包括牛磺酸去氢胆酸、牛磺酸、脱氧胆酸（DCA）、糖胆酸（GCA）、牛磺酸-α-胆酸、牛磺酸-ω-胆酸和羟基去氧胆酸（HDCA）。脑内牛磺胆酸、牛磺去氢胆酸、牛磺酸-ω-胆酸、牛磺酸-β-胆酸、脱氧胆酸和石胆酸（LCA）浓度也有变化。综上所述，FXR基因敲除小鼠的研究结果表明，FXR有助于大脑不同区域多种神经递质系统的稳态，并调节神经行为。这种效果似乎至少部分是由胆汁酸介导的，胆汁酸已知会穿过血脑屏障（BBB），诱发潜在的神经毒性。
Farnesoid X receptor (FXR) is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in an unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic, and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid (DCA), glycocholic acid (GCA), tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid (HDCA). There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid (LCA). Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier (BBB) inducing potential neurotoxicity.
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影响因子：
3.6
作者：
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通讯作者：
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影响因子：
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作者：
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作者：
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通讯作者：
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DOI：
10.1016/s0006-291x(02)02550-0
发表时间：
2002-11-15
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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