title: 7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome.
abstract: Fragile X syndrome (FXS) is characterized by immature dendritic spine architectures and cognitive impairment. 7, 8-Dihydroxyflavone (7, 8-DHF) has recently been identified as a high affinity tropomyosin receptor kinase B (TrkB) agonist. The purpose of this paper was to examine the utility of 7, 8-DHF as an effective pharmacotherapeutic agent that targets dendritic pathology and cognitive impairments in FXS mutant. We synthesized pharmacologic, behavioral, and biochemical approaches to examine the effects of 7, 8-DHF on spatial and fear memory functions, and morphological spine abnormalities in fragile X mental retardation 1 (Fmr1) gene knock-out mice. The study found that 4 weeks of treatment with 7, 8-DHF improved spatial and fear memory, and ameliorated morphological spine abnormalities including the number and elongation of spines in the hippocampus and amygdala. Further mechanism analysis revealed that 7, 8-DHF enhanced the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluA1 receptor, but reduced the normal levels of GluA2 at the synapses in Fmr1. Potentially related to drug-induced changes in AMPA receptor subunits, 7, 8-DHF at the synapses led to phosphorylation of specific serine sites on subunits Ser818 and Ser813 of GluA1, and Ser880 of GluA2, as well as phosphorylation of TrkB, calcium/calmodulin-dependent protein kinase II, and protein kinase C. However, 7, 8-DHF neither affected behavioral performance nor increased TrkB phosphorylation in WT mice, which suggested that it had FXS-specific correcting effect. Altogether, these results demonstrated that 7, 8-DHF improved learning and memory, and reduced abnormalities in spine morphology, thus providing a potential pharmacotherapeutic strategy for FXS.
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Tian
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China. Electronic address: yanzeng11@yahoo.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Yilan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Xiuxue
authors.initials: X
authors.lastname: Yuan
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Shumin
authors.initials: S
authors.lastname: Liu
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Lu
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Daan
authors.initials: D
authors.lastname: Fu
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Brain Stimulation and Neurophysiology, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA; Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: McClintock
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D047309:Flavones / Q000494:pharmacology / Q000627:therapeutic use*; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018091:Receptors, AMPA / Q000096:biosynthesis*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D047309:Flavones; D018091:Receptors, AMPA; C485383:6,7-dihydroxyflavone
keywords: 7, 8-Dihydroxyflavone; AMPA receptor; BDNF; Fragile X syndrome; TrkB agonist