Early 7,8-Dihydroxyflavone Administration Ameliorates Synaptic and Behavioral Deficits in the Young FXS Animal Model by Acting on BDNF-TrkB Pathway.

Abstract

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and the most common cause of autism spectrum disorders. FXS patients exhibit severe syndromic features and behavioral alterations, including anxiety, hyperactivity, impulsivity, and aggression, in addition to cognitive impairment and seizures. At present, there are no effective treatments or cures for FXS. Previously, we have found the divergence of BDNF-TrkB signaling trajectories is associated with spine defects in early postnatal developmental stages of Fmr1 KO mice. Here, young fragile X mice were intraperitoneal injection with 7,8-Dihydroxyflavone (7,8-DHF), a high affinity tropomyosin receptor kinase B (TrkB) agonist. 7,8-DHF ameliorated morphological abnormities in dendritic spine and synaptic structure and rescued synaptic and hippocampus-dependent cognitive dysfunction. These observed improvements of 7,8-DHF involved decreased protein levels of BDNF, p-TrkBY816, p-PLCγ, and p-CaMKII in the hippocampus. In addition, 7,8-DHF intervention in primary hippocampal neurons increased p-TrkBY816 and activated the PLCγ1-CaMKII signaling pathway, leading to improvement of neuronal morphology. This study is the first to account for early life synaptic impairments, neuronal morphological, and cognitive delays in FXS in response to the abnormal BDNF-TrkB pathway. Present studies provide novel evidences about the effective early intervention in FXS mice at developmental stages and a strategy to produce powerful impacts on neural development, synaptic plasticity, and behaviors.