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Cited by 109Neuroscience and Neuropharmacology ResearchDrug Transport and Resistance MechanismsNeurotransmitter Receptor Influence on Behavior

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

Open access
Huang, Fei, Wang, Tingting, Lan, Yunyi, Yang, Li, Pan, Weihong, Zhu, Yonghui, Lv, Boyang, Wei, Yuting, Shi, Hailian, Wu, Hui, Zhang, Beibei, Wang, Jie, Duan, Xiaofeng, Hu, Zhibi, Wu, Xiaojun·2015·Frontiers in Behavioral Neuroscience
DOI 10.3389/fnbeh.2015.00070PMC PMC4378301
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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.

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Crossref · 10.3389/fnbeh.2015.00070

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Figures

Figure 1 Experimental paradigm of the behavioral tests.
Figure 1 Experimental paradigm of the behavioral tests.CC BY · PubMed Central
Figure 2 FXR KO mice showed less depressive-like behavior. In comparison with wild-type controls, FXR KO mice did not have reduced immobility time in the FST (B), but exhibited significantly decreased immobility time in the TST (A). N = 12/group; ** p < 0.01.
Figure 2 FXR KO mice showed less depressive-like behavior. In comparison with wild-type controls, FXR KO mice did not have reduced immobility time in the FST (B), but exhibited significantly decreased immobility time in the TST (A). N = 12/group; ** p < 0.01.CC BY · PubMed Central
Figure 3 FXR KO mice had low levels of anxiety-related behavior. In comparison with wild-type controls, FXR KO mice had high ratio of central distance/total distance in the OFT (A). Moreover, the KO mice had a greater tendency to explore (B) and to stay in the open arm in the EPMT (C). N = 12/group; *p < 0.05; **p < 0.01.
Figure 3 FXR KO mice had low levels of anxiety-related behavior. In comparison with wild-type controls, FXR KO mice had high ratio of central distance/total distance in the OFT (A). Moreover, the KO mice had a greater tendency to explore (B) and to stay in the open arm in the EPMT (C). N = 12/group; *p < 0.05; **p < 0.01.CC BY · PubMed Central
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.
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.CC BY · PubMed Central
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.
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.CC BY · PubMed Central
Figure 6 FXR KO down-regulated hippocampal GAD65 of the mice. (A) Western blotting analysis of GAD65, GAT1, GABAARα5, and GABAARβ2/3; (B) Gray intensity comparison. N = 8/group; * p < 0.05.
Figure 6 FXR KO down-regulated hippocampal GAD65 of the mice. (A) Western blotting analysis of GAD65, GAT1, GABAARα5, and GABAARβ2/3; (B) Gray intensity comparison. N = 8/group; * p < 0.05.CC BY · PubMed Central
Figure 7 FXR KO increased cerebellar GAT1. (A) Western blotting analysis of GAD65, GAT1, GABAARα5, GABAARβ2/3, 5-HT1A, and SLC6A2. (B) Gray intensity comparison. N = 8/group; +p < 0.1.
Figure 7 FXR KO increased cerebellar GAT1. (A) Western blotting analysis of GAD65, GAT1, GABAARα5, GABAARβ2/3, 5-HT1A, and SLC6A2. (B) Gray intensity comparison. N = 8/group; +p < 0.1.CC BY · PubMed Central
Figure 8 FXR KO on BAs in serum. In comparison with wild-type controls, FXR KO mice showed higher concentrations of THDCA, TCA, Tω MCA, and TαMCA in T-BAs in serum (A); higher concentrations of GCA, HDCA, and DCA in U-BAs in serum (B). N = 16/group; * p < 0.05; ** p < 0.01.
Figure 8 FXR KO on BAs in serum. In comparison with wild-type controls, FXR KO mice showed higher concentrations of THDCA, TCA, Tω MCA, and TαMCA in T-BAs in serum (A); higher concentrations of GCA, HDCA, and DCA in U-BAs in serum (B). N = 16/group; * p < 0.05; ** p < 0.01.CC BY · PubMed Central
Figure 9 FXR KO on BAs in brain. In comparison with wild-type controls, FXR KO mice displayed higher concentrations of TCA, TCDCA, Tω MCA, and DCA (A) but lower concentrations of TβMCA and LCA in brain (B). N = 7–10/group; * p < 0.05; +p < 0.1.
Figure 9 FXR KO on BAs in brain. In comparison with wild-type controls, FXR KO mice displayed higher concentrations of TCA, TCDCA, Tω MCA, and DCA (A) but lower concentrations of TβMCA and LCA in brain (B). N = 7–10/group; * p < 0.05; +p < 0.1.CC BY · PubMed Central

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Metadata

Authors
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.
Affiliations
  • Shanghai University of Traditional Chinese Medicine (CN)
  • Pennington Biomedical Research Center (US)
  • Shanghai East Hospital (CN)
Corresponding author
Wu, Xiaojun
ORCID
Venue
Frontiers in Behavioral Neuroscience
Publisher
Frontiers Media SA
Published
2015-03-30
Volume
9
Pages
70-70
ISSN
1662-5153 (ISSN-L)
DOI
10.3389/fnbeh.2015.00070
PMC
PMC4378301
OpenAlex
W2151789409
Cited by
109
References
52
Citations by year
2026: 7 · 2025: 15 · 2024: 21 · 2023: 8 · 2022: 18 · 2021: 10 · 2020: 8 · 2019: 6 · 2018: 6 · 2017: 3 · 2016: 6
FWCI
2.32
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
farnesoid X receptor, FXR knockout mice, bile acids, neurotransmitter systems, neurobehavior, depression-like behavior, anxiety-like behavior, motor activity, memory impairment, motor coordination, GABA synthesis, GAD65, glutamatergic neurotransmission, GABAergic neurotransmission, serotonergic neurotransmission, norepinephrine, hippocampus, cerebellum, blood-brain barrier, neurotoxicity, bile acid homeostasis

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