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

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.
Nature Communications (Impact Factor: 11.47). 10/2013; 4:2628. DOI: 10.1038/ncomms3628
Source: PubMed


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.

28 Reads
  • Source
    • "Corticosteroid signaling is regulated in part by serine/threonine kinases, including cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3␤ (GSK3␤) [19] [20] [21] [22] [23]. These kinases orchestrate various cellular functions including neuronal maturation, neurotransmitter release, axon and dendritic organization, neural trafficking, transport, and signal transduction [24] [25] [26]; both are implicated in the progression of several major psychiatric illnesses and neurodegenerative diseases [27] [28] [29]. Studies have shown that GSK3␤ and CDK5 are responsive to alcohol [30] [31] [32], although the effects generated by a moderate in vivo prenatal exposure and the duration of such effects remain unclear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fetal alcohol spectrum disorders (FASDs) are the number one cause of preventable mental retardation. An estimated 2-5% of children are diagnosed as having a FASD. While it is known that children prenatally exposed to alcohol experience cognitive deficits and a higher incidence of psychiatric illness later in life, the pathways underlying these abnormalities remain uncertain. GSK3β and CDK5 are protein kinases that are converging points for a vast number of signaling cascades, including those controlling cellular processes critical to learning and memory. We investigated whether levels of GSK3β and CDK5 are affected by moderate prenatal alcohol exposure (PAE), specifically in the hippocampus and medial frontal cortex of the adolescent mouse. In the present work we utilized immunoblotting techniques to demonstrate that moderate PAE increased hippocampal p35 and β-catenin, and decreased total levels of GSK3β, while increasing GSK3β Ser9 and Tyr216 phosphorylation. Interestingly, different alterations were seen in the medial frontal cortex where p35 and CDK5 were decreased and increased total GSK3β was accompanied by reduced Tyr216 of the enzyme. These results suggest that kinase dysregulation during adolescence might be an important contributing factor to the effects of PAE on hippocampal and medial frontal cortical functioning; and by extension, that global modulation of these kinases may produce differing effects depending on brain region.
    Toxicology Reports 12/2014; 1. DOI:10.1016/j.toxrep.2014.08.005
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuropathic pain and sensory abnormalities are a debilitating secondary consequence of spinal cord injury (SCI). Maladaptive structural plasticity is gaining recognition for its role in contributing to the development of post SCI pain syndromes. We previously demonstrated that excitotoxic induced SCI dysesthesias are associated with enhanced dorsal root ganglia (DRG) neuronal outgrowth. Although glycogen synthase kinase-3β (GSK-3β) is a known intracellular regulator neuronal growth, the potential contribution to primary afferent growth responses following SCI are undefined. We hypothesized that SCI triggers inhibition of GSK-3β signaling resulting in enhanced DRG growth responses, and that PI3K mediated activation of GSK-3β can prevent this growth and the development of at-level pain syndromes. Excitotoxic SCI using intraspinal quisqualic acid (QUIS) resulted in inhibition of GSK-3β in the superficial spinal cord dorsal horn and adjacent DRG. Double immunofluorescent staining showed that GSK-3β(P) was expressed in DRG neurons, especially small nociceptive, CGRP and IB4-positive neurons. Intrathecal administration of a potent PI3-kinase inhibitor (LY294002), a known GSK-3β activator, significantly decreased GSK-3β(P) expression levels in the dorsal horn. QUIS injection resulted in early (3 days) and sustained (14 days) DRG neurite outgrowth of small and subsequently large fibers that was reduced with short term (3 days) administration of LY294002. Furthermore, LY294002 treatment initiated on the date of injury, prevented the development of overgrooming, a spontaneous at-level pain related dysesthesia. QUIS induced SCI resulted in inhibition of GSK-3β in primary afferents and enhanced at-level DRG intrinsic growth (neurite elongation and initiation). Early PI3K mediated activation of GSK-3β attenuated QUIS-induced DRG neurite outgrowth and prevented the development of at-level dysesthesias.
    Molecular Pain 06/2015; 11(1):35. DOI:10.1186/s12990-015-0041-2 · 3.65 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated chloride channels - namely, type A GABA (GABAA) and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that postsynaptic gephyrin clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, post-translational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules. Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission.
    Nature Reviews Neuroscience 02/2014; 15(3):141-156. DOI:10.1038/nrn3670 · 31.43 Impact Factor
Show more


28 Reads
Available from