title: Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway.
abstract: It is evidenced that inflammation is involved in the pathogenesis of anxiety disorder, as well as the dysfunction of glutamate neurotransmission in the central nervous system (CNS). Chemokine CXCL12 has been reported taking part in the regulation of neurotransmitter release, however, the roles of CXCL12 in the development of anxiety are still unclear. In this study, we found that intraperitoneal (i.p) injection of lipopolysaccharide (LPS) induced anxiety-like behaviors in adult mice as measured by elevated plus-maze test (EPM) and open field test (OFT). Astrocytes were responsible for CXCL12 induction upon LPS challenge in hippocampus and amygdala, and microinjection of CXCL12 into amygdala induced mice anxiety-like behaviors. AMD3100, which is an antagonist for CXCL12 receptor CXCR4, prevented the anxiety behaviors induced by microinjection of CXCL12 into amygdala as well as injection i.p of LPS. Knockdown of CXCR4 expression in neurons using short hairpin RNAs (shRNAs) significantly blocked anxiety behaviors mediated by CXCL12 i.c injection. Furthermore, AMD3100 or shCXCR4 prevented the impairment of nesting ability induced by CXCL12 in mice. Whole-cell patch-clamp recordings in the neurons of basolateral amygdala (BLA) revealed that CXCL12 enhanced glutamatergic transmission by increasing sEPSC frequency in the amygdala. AMD3100 inhibited the excitatory glutamatergic neural transmission and involved in the development of anxiety through CXCR4. These findings provide direct evidence that alterations of CXCL12 in BLA play critical roles in the development of anxiety induced by systemic inflammation and that CXCR4 may be a potential therapeutic target for inflammation-induced anxiety.
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: Y Y
authors.initials: YY
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: T
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China.
authors.forename: S B
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China. Electronic address: minggao@fmmu.edu.cn.
authors.forename: M G
authors.initials: MG
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, PR China. Electronic address: yumeiwu@fmmu.edu.cn.
authors.forename: Y M
authors.initials: YM
authors.lastname: Wu
mesh_terms: D000818:Animals; D001007:Anxiety / Q000178:diet therapy / Q000209:etiology* / Q000378:metabolism*; D066272:Basolateral Nuclear Complex / Q000187:drug effects / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism* / Q000494:pharmacology; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: Anxiety; CXCL12; CXCR4; Glutamate; Lipopolysaccharide; Neurotransmission