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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 impaired cognitive ability of the mice. In comparison with wild-type controls, FXR KO mice displayed decreased latency (A) but increased number of errors (B) in PAT. N = 12/group; * p < 0.05.
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Figure 4: FXR KO impaired cognitive ability of the mice. In comparison with wild-type controls, FXR KO mice displayed decreased latency (A) but increased number of errors (B) in PAT. N = 12/group; * p < 0.05.

Mentions: FXR deletion impaired the emotional memory of mice. In PAT, compared with the controls, the latency for FXR KO mice to enter the dark chamber on the test day was significantly shorter [Figure 4A; t(21) = 2.231, p < 0.05]. Meanwhile, the number of entries into the dark chamber increased markedly in the KO mice [Figure 4B, t(20) = 2.546, p < 0.05]. All these results indicate that the FXR deletion impaired the cognitive ability of mice.


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 impaired cognitive ability of the mice. In comparison with wild-type controls, FXR KO mice displayed decreased latency (A) but increased number of errors (B) in PAT. N = 12/group; * p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: FXR KO impaired cognitive ability of the mice. In comparison with wild-type controls, FXR KO mice displayed decreased latency (A) but increased number of errors (B) in PAT. N = 12/group; * p < 0.05.
Mentions: FXR deletion impaired the emotional memory of mice. In PAT, compared with the controls, the latency for FXR KO mice to enter the dark chamber on the test day was significantly shorter [Figure 4A; t(21) = 2.231, p < 0.05]. Meanwhile, the number of entries into the dark chamber increased markedly in the KO mice [Figure 4B, t(20) = 2.546, p < 0.05]. All these results indicate that the FXR deletion impaired the cognitive ability of mice.

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