title: Activity-dependent regulation of dendritic growth and maintenance by glycogen synthase kinase 3β.
abstract: Activity-dependent dendritic development represents a crucial step in brain development, but its underlying mechanisms remain to be fully elucidated. Here we report that glycogen synthase kinase 3β (GSK3β) regulates dendritic development in an activity-dependent manner. We find that GSK3β in somatodendritic compartments of hippocampal neurons becomes highly phosphorylated at serine-9 upon synaptogenesis. This phosphorylation-dependent GSK3β inhibition is mediated by neurotrophin signalling and is required for dendritic growth and arbourization. Elevation of GSK3β activity leads to marked shrinkage of dendrites, whereas its inhibition enhances dendritic growth. We further show that these effects are mediated by GSK3β regulation of surface GABAA receptor levels via the scaffold protein gephyrin. GSK3β activation leads to gephyrin phosphorylation to reduce surface GABAA receptor clusters, resulting in neuronal hyperexcitability that causes dendrite shrinkage. These findings thus identify GSK3β as a key player in activity-dependent regulation of dendritic development by targeting the excitatory-inhibitory balance of the neuron.
authors.affiliation: 1] Department of Cell Biology and Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA [2] Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Rui
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Myers
authors.forename: Kuai
authors.initials: K
authors.lastname: Yu
authors.forename: Ariel
authors.initials: A
authors.lastname: Wise
authors.forename: Angel L
authors.initials: AL
authors.lastname: De Blas
authors.forename: H Criss
authors.initials: HC
authors.lastname: Hartzell
authors.forename: James Q
authors.initials: JQ
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism* / Q000648:ultrastructure; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D011963:Receptors, GABA-A; C073441:gephyrin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3