Early 7,8-Dihydroxyflavone Administration Ameliorates Synaptic and Behavioral Deficits in the Young FXS Animal Model
Yu-Shan Chen1,2, Si-Ming Zhang1,2, Wei Tan2
1Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, 430065, China.
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.
Insights
Early intervention with 7,8-Dihydroxyflavone (7,8-DHF) improved cognitive and synaptic deficits in Fragile X syndrome (FXS) mouse models by targeting the BDNF-TrkB pathway.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Fragile X syndrome (FXS) is a leading inherited cause of intellectual disability and autism spectrum disorder.
- FXS is characterized by cognitive impairment, seizures, and behavioral issues, with no current effective treatments.
- Abnormalities in the BDNF-TrkB signaling pathway are linked to synaptic defects in early development of FXS models.
Purpose of the Study:
- To investigate the therapeutic potential of 7,8-Dihydroxyflavone (7,8-DHF), a TrkB agonist, for FXS.
- To explore the effects of 7,8-DHF on synaptic structure, cognitive function, and neuronal morphology in FXS mouse models.
- To elucidate the underlying molecular mechanisms involving the BDNF-TrkB pathway.
Main Methods:
- Young Fmr1 KO mice (FXS model) were treated with intraperitoneal injections of 7,8-DHF.
- Morphological analysis of dendritic spines and synaptic structures was performed.
- Cognitive functions were assessed using hippocampus-dependent tasks.
- Protein levels of BDNF, p-TrkB, p-PLCγ, and p-CaMKII were measured in the hippocampus.
- Primary hippocampal neurons were treated with 7,8-DHF to study pathway activation.
Main Results:
- 7,8-DHF treatment ameliorated dendritic spine and synaptic structure abnormalities in FXS mice.
- Cognitive dysfunction in FXS mice was rescued by 7,8-DHF intervention.
- 7,8-DHF decreased hippocampal levels of BDNF, p-TrkBY816, p-PLCγ, and p-CaMKII.
- In primary neurons, 7,8-DHF increased p-TrkBY816 and activated the PLCγ1-CaMKII pathway, improving neuronal morphology.
Conclusions:
- This study demonstrates that early intervention with 7,8-DHF can effectively improve synaptic and cognitive deficits in an FXS mouse model.
- The therapeutic effects of 7,8-DHF are mediated through the BDNF-TrkB signaling pathway, impacting neuronal development and plasticity.
- Targeting the BDNF-TrkB pathway offers a promising therapeutic strategy for FXS, particularly with early developmental intervention.
