Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at...Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.展开更多
Objective:To investigate the effect of electroacupuncture on CREB/BDNF/TrkB signaling pathway in hippocampus of depressed rats.Methods:The depression rat model was established by chronic unpredictable stress(CUMS)comb...Objective:To investigate the effect of electroacupuncture on CREB/BDNF/TrkB signaling pathway in hippocampus of depressed rats.Methods:The depression rat model was established by chronic unpredictable stress(CUMS)combined with solitary rearing.The rats were randomly divided into blank group,model group,electroacupuncture group and fluoxetine group,with 10 rats in each group.In the electroacupuncture group,‘Baihui',‘Shenting',‘Hegu'and‘Taichong'were selected.Acupuncture was performed 1 h before modeling every day,and the needles were retained for 20 min,once a day for 21 d.Fluoxetine group:Fluoxetine(10 mg/kg,1 mg/mL)was intragastrically administered 1 h before modeling for 21 d.The changes of body weight,the number of standing and the distance of movement in open field test,the immobility time of forced swimming test were observed.The contents of 5-HT,DA and NE in serum were detected by ELISA.The expression of BDNF,CREB and TrkB in hippocampus was detected by Western blot.The expression of BDNF and CREB mRNA in hippocampus was detected by real-time fluorescence quantitative PCR.Results:After modeling intervention:Compared with the blank group,the body weight,the number of standing,the distance of movement,the content of serum 5-HT,DA and NE,the expression of BDNF,CREB and TrkB in the hippocampus of the model group were significantly decreased(all P<0.01),and the immobility time was significantly increased(P<0.01).Compared with the model group,the body weight,the number of standing,the distance of movement,the content of 5-HT,DA and NE in serum,the expression of BDNF,CREB and TrkB in hippocampus were significantly increased(all P<0.05),and the immobility time was significantly decreased(P<0.05)in the EA group and fluoxetine group.There was no significant difference between the electroacupuncture group and the fluoxetine group(P>0.05).Conclusion:EA can significantly improve the symptoms of depression in rats,and its mechanism may be related to the regulation of BDNF/TrkB/CREB signaling pathway-related proteins in hippocampus,increase the content of monoamine neurotransmitters 5-HT,NE and DA,resulting in antidepressant effect.展开更多
基金supported by Postdoc Fellowship from the Foundation for Angelman Syndrome Therapeutics(FT2022-005 to JM,PD2023-001 to XY,and FT2024-001 to YAH)STTR R41 MH118747(to JM)。
文摘Tropomyosin receptor kinase B(TrkB)signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory.The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre-or postsynaptic TrkB resulting in the strengthening of synapses,reflected by long-term potentiation.Postsynaptically,the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca^(2+)/calmodulin-dependent protein kinaseⅡand phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation.In this review,we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders.A reduction of TrkB signaling has been observed in neurodegenerative disorders,such as Alzheimer's disease and Huntington's disease,and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression.Treatment with brain-derived neurotrophic factor is problematic,due to poor pharmacokinetics,low brain penetration,and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform.Although TrkB agonists and antibodies that activate TrkB are being intensively investigated,they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions.Targeting TrkB–postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.
基金supported by Scientific Research Project of Traditional Chinese Medicine Administration of Shanxi Province(2019ZYYC036)。
文摘Objective:To investigate the effect of electroacupuncture on CREB/BDNF/TrkB signaling pathway in hippocampus of depressed rats.Methods:The depression rat model was established by chronic unpredictable stress(CUMS)combined with solitary rearing.The rats were randomly divided into blank group,model group,electroacupuncture group and fluoxetine group,with 10 rats in each group.In the electroacupuncture group,‘Baihui',‘Shenting',‘Hegu'and‘Taichong'were selected.Acupuncture was performed 1 h before modeling every day,and the needles were retained for 20 min,once a day for 21 d.Fluoxetine group:Fluoxetine(10 mg/kg,1 mg/mL)was intragastrically administered 1 h before modeling for 21 d.The changes of body weight,the number of standing and the distance of movement in open field test,the immobility time of forced swimming test were observed.The contents of 5-HT,DA and NE in serum were detected by ELISA.The expression of BDNF,CREB and TrkB in hippocampus was detected by Western blot.The expression of BDNF and CREB mRNA in hippocampus was detected by real-time fluorescence quantitative PCR.Results:After modeling intervention:Compared with the blank group,the body weight,the number of standing,the distance of movement,the content of serum 5-HT,DA and NE,the expression of BDNF,CREB and TrkB in the hippocampus of the model group were significantly decreased(all P<0.01),and the immobility time was significantly increased(P<0.01).Compared with the model group,the body weight,the number of standing,the distance of movement,the content of 5-HT,DA and NE in serum,the expression of BDNF,CREB and TrkB in hippocampus were significantly increased(all P<0.05),and the immobility time was significantly decreased(P<0.05)in the EA group and fluoxetine group.There was no significant difference between the electroacupuncture group and the fluoxetine group(P>0.05).Conclusion:EA can significantly improve the symptoms of depression in rats,and its mechanism may be related to the regulation of BDNF/TrkB/CREB signaling pathway-related proteins in hippocampus,increase the content of monoamine neurotransmitters 5-HT,NE and DA,resulting in antidepressant effect.
