Activity-Dependent Regulation of Dendritic Growth and Maintenance by Glycogen Synthase Kinase 3β

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 signaling and is required for dendritic growth and arborization. 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 GABA(A) receptor levels via the scaffold protein gephyrin. GSK3β activation leads to gephyrin phosphorylation to reduce surface GABA(A) 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.