TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory.
The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB participate in diverse neuronal functions, including activity-dependent synaptic plasticity that is crucial for learning and memory. On binding to BDNF, TrkB is not only autophosphorylated at tyrosine residues but also undergoes serine phosphorylation at S478 by the serine/threonine kinase cyclin-dependent kinase 5 (Cdk5). However, the in vivo function of this serine phosphorylation remains unknown. We generated knock-in mice lacking this serine phosphorylation (Trkb(S478A/S478A) mice) and found that the TrkB phosphorylation-deficient mice displayed impaired spatial memory and compromised hippocampal long-term potentiation (LTP). S478 phosphorylation of TrkB regulates its interaction with the Rac1-specific guanine nucleotide exchange factor TIAM1, leading to activation of Rac1 and phosphorylation of S6 ribosomal protein during activity-dependent dendritic spine remodeling. These findings reveal the importance of Cdk5-mediated S478 phosphorylation of TrkB in activity-dependent structural plasticity, which is crucial for LTP and spatial memory formation.
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.
Kwok-On
KO
Lai
Alan S L
AS
Wong
Man-Chun
MC
Cheung
Pei
P
Xu
Zhuoyi
Z
Liang
Ka-Chun
KC
Lok
Hui
H
Xie
Mary E
ME
Palko
Wing-Ho
WH
Yung
Lino
L
Tessarollo
Zelda H
ZH
Cheung
Nancy Y
NY
Ip
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D010766:Phosphorylation / Q000235:genetics; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D012694:Serine / Q000378:metabolism; D016622:Silver Staining; D013037:Spatial Behavior / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D013997:Time Factors; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D020662:Guanine Nucleotide Exchange Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011810:Quinoxalines; D016708:Synaptophysin; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; C089495:neuronal Cdk5 activator (p25-p35); C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D012694:Serine; D020813:Receptor, trkB; D051360:Cyclin-Dependent Kinase 5; D019893:Ribosomal Protein S6 Kinases; D051528:Guanylate Kinases; D020830:rac1 GTP-Binding Protein