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Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior.

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 - Front Behav Neurosci (2015)

Bottom Line: They had impaired memory and reduced motor coordination.FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex.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.

View Article: PubMed Central - PubMed

Affiliation: The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

FXR KO altered motor performance of the mice. In comparison with wild-type controls, FXR KO mice fell from the rod more often in the RRT (A) but seemed to be hyperactive in the OFT (B). N = 12/group; ** p < 0.01.
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Figure 5: FXR KO altered motor performance of the mice. In comparison with wild-type controls, FXR KO mice fell from the rod more often in the RRT (A) but seemed to be hyperactive in the OFT (B). N = 12/group; ** p < 0.01.

Mentions: When FXR was deleted, the mice seemed to lose motor control. In the RRT, FXR KO mice lost their coordination of body and fell more easily from the rotating rods [Figure 5A; t(20) = 2.927, p < 0.01]. However, KO mice appeared to be hyperactive. The total distance traveled in OFT was much longer in the KO mice than their wild-type controls [Figure 5B; t(20) = 3.146, p < 0.01].


Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior.

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 - Front Behav Neurosci (2015)

FXR KO altered motor performance of the mice. In comparison with wild-type controls, FXR KO mice fell from the rod more often in the RRT (A) but seemed to be hyperactive in the OFT (B). N = 12/group; ** p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4378301&req=5

Figure 5: FXR KO altered motor performance of the mice. In comparison with wild-type controls, FXR KO mice fell from the rod more often in the RRT (A) but seemed to be hyperactive in the OFT (B). N = 12/group; ** p < 0.01.
Mentions: When FXR was deleted, the mice seemed to lose motor control. In the RRT, FXR KO mice lost their coordination of body and fell more easily from the rotating rods [Figure 5A; t(20) = 2.927, p < 0.01]. However, KO mice appeared to be hyperactive. The total distance traveled in OFT was much longer in the KO mice than their wild-type controls [Figure 5B; t(20) = 3.146, p < 0.01].

Bottom Line: They had impaired memory and reduced motor coordination.FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex.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.

View Article: PubMed Central - PubMed

Affiliation: The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus