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 known 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 of 7,8-Dihydroxy avone (7,8-DHF), which is a high a nity 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 in young FXS mice. These observed improvement of 7,8-DHF involved decreased protein levels of BDNF, p-TrkB Y816 , p-PLCγ, and p-CaMKII in the hippocampus. In addition, 7,8-DHF intervention in primary hippocampal neurons increased p-TrkB Y816 through activating the PLCγ1-CaMKII signaling pathway leading to improvement of neuronal morphology.This study is the rst 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 as a strategy to produce powerful impacts on neural development, synaptic plasticity and behaviors.

7,8-Dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer’s disease ( Zhang et al, 2014a ; Devi and Ohno, 2012 ; Bollen et al, 2013 ; Castello et al, 2014 ; Aytan et al, 2018 ; Gao et al, 2016 ; Akhtar et al, 2021 ; Hsiao et al, 2014 ), depression ( Blugeot et al, 2011 ; Zhang et al, 2014b ; Yao et al, 2016 ; Zhang et al, 2016 ; Li et al, 2022 ; Amin et al, 2020 ), schizophrenia ( Jaehne et al, 2021 ; Han et al, 2016 ; Yang et al, 2014 ; Han et al, 2017 ; Ren et al, 2013 ), epilepsy ( Becker et al, 2015 ; Guarino et al, 2022 ), and autism ( Johnson et al, 2012 ; Kang et al, 2017 ; Lee and Han, 2019 ; Chen et al, 2023 ). Although PLP deficiency is thought to contribute to the respective human conditions ( di Salvo et al, 2012 ; Majewski et al, 2016 ; Sorolla et al, 2016 ), PLP-dependent processes have not yet been considered in the context of 7,8-DHF-induced effects.…”

7,8-Dihydroxyflavone is a direct inhibitor of pyridoxal phosphatase

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer's disease (49)(50)(51)(52)(53)(54)(55)(56), depression (57)(58)(59)(60)(61)(62), schizophrenia (63)(64)(65)(66)(67), or epilepsy (68,69), as well as in rodent models of autism (70)(71)(72)(73).…”

“…The discovery of 7,8-DHF as a direct PDXP inhibitor was unexpected. Interestingly, numerous in vivo studies have reported the effectiveness of 7,8-DHF in brain disorder models, including rodent models of Alzheimer's disease (50)(51)(52)(53)(54)(55)(56)(57), depression (58)(59)(60)(61)(62)(63), schizophrenia (64)(65)(66)(67)(68), epilepsy (69,70) and autism (71)(72)(73)(74). Although PLP deficiency is thought to contribute to the respective human conditions (3,75,76), PLP-dependent processes have not yet been considered in the context of 7,8-DHF-induced effects.…”

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model

“…Brain-derived neurotrophic factor (BDNF) plays an important role in the survival, growth and differentiation of neuronal cells, while tyrosine kinase receptor B (TrkB) is the main receptor of BDNF which performs a regulatory role in downstream signaling pathways after binding to BDNF and activating its biological effects. Studies have shown alterations in the expressions of BDNF and TrkB in the hippocampus of autism mouse model, indicating that these proteins are associated with autism [6]. In addition, it was found that simvastatin improved the behavioral performance of VPA-induced autism model in mice [7].…”