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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.
AuthorsMi Tian, Yan Zeng, Yilan Hu, Xiuxue Yuan, Shumin Liu, Jie Li, Pan Lu, Yao Sun, Lei Gao, Daan Fu, Yi Li, Shasha Wang, Shawn M McClintock
JournalNeuropharmacology (Neuropharmacology) Vol. 89 Pg. 43-53 (Feb 2015) ISSN: 1873-7064 [Electronic] England
PMID25229717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • 6,7-dihydroxyflavone
  • Flavones
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 1
Topics
  • Animals
  • Cognition Disorders (drug therapy, metabolism, pathology)
  • Dendritic Spines (drug effects, metabolism, pathology)
  • Disease Models, Animal
  • Flavones (pharmacology, therapeutic use)
  • Fragile X Syndrome (drug therapy, metabolism, pathology)
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, AMPA (biosynthesis)
  • Synapses (drug effects, metabolism, pathology)

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