7, 8-Dihydroxyflavone induces synapse expression of AMPA GluA1 and ameliorates cognitive and spine abnormalities in a mouse model of fragile X syndrome

Neuropharmacology. 2015 Feb;89:43-53. doi: 10.1016/j.neuropharm.2014.09.006. Epub 2014 Sep 16.

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.

Keywords: 7, 8-Dihydroxyflavone; AMPA receptor; BDNF; Fragile X syndrome; TrkB agonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cognition Disorders / drug therapy
  • Cognition Disorders / metabolism*
  • Cognition Disorders / pathology
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism*
  • Dendritic Spines / pathology
  • Disease Models, Animal*
  • Flavones / pharmacology
  • Flavones / therapeutic use*
  • Fragile X Syndrome / drug therapy
  • Fragile X Syndrome / metabolism*
  • Fragile X Syndrome / pathology
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, AMPA / biosynthesis*
  • Synapses / drug effects
  • Synapses / metabolism*
  • Synapses / pathology

Substances

  • 6,7-dihydroxyflavone
  • Flavones
  • Receptors, AMPA
  • glutamate receptor ionotropic, AMPA 1