Synaptic plasticity is essential for the development of brain, learning and memory. Hebbian-type plasticity such as long-term potentiation and long-term depression is rapid and synapse-specific modification. In contrast, homeostatic plasticity involves global modification of synapses, operates over longer timescales, and is believed to be crucial for the maintaining and orchestrating neuronal network function. Hebbian-type plasticity is mediated mainly by the trafficking of AMPA receptors but not much is known for the mechanisms of homeostatic plasticity. Recently, activity-dependent protein turnover at the synapses by ubiquitin-proteasome system has emerged as crucial mechanisms associated with various types of synaptic plasticity including homeostatic plasticity. However, it is unknown how activity orchestrates concomitant ubiquitination/degradation and recruitment of specific group of proteins at synapses. Among the activity-regulated proteins, GKAP is one of the major scaffolding proteins in the postsynaptic densities and provides a molecular link for PSD-95/NMDA receptor complex and Shank/Homer. Our preliminary studies suggest that activity controls the recruitment and removal of GKAP from synapses, both through Ca2????dependent protein kinase II (CaMKII). Further, we found that the activity-dependent turnover of GKAP is required for synaptic scaling in hippocampal neurons. In this proposal, we will investigate the molecular mechanisms by which CaMKII controls ubiquitination/degradation or recruitment of GKAP to synapses, and the functional significance of the GKAP turnover at the synapses in various types of synaptic plasticity.
Aim 1 will map the CaMKII phosphorylation site(s) and ubiquitinated lys site(s) that induce ubiquitination of GKAP, using a combination of mutagenesis and biochemical assays.
Aim 2 focuses on understanding the role of DLC, MyoV, and CaMKII for GKAP recruitment to synapses by molecular genetic approaches. We will also perform real-time imaging to understand dynamic GKAP trafficking with greater spatio-temporal resolution.
Aim 3 will assess the functional significance of GKAP removal/recruitment at synapses for the activity-dependent modification of synapse compositions and various forms of synaptic plasticity, by using GKAP mutants lacking the activity- dependent turnover. Since aberrant synaptic plasticity is implicated for a variety of neurological and neuropsychiatric diseases, the proposed studies will not only allow us to gain novel and fundamental insight into the molecular mechanisms for long-lasting changes in synapse compositions but also are relevant to these brain diseases.

Public Health Relevance

Synaptic plasticity is a fundamental mechanism by which neurons store experience and forms a foundation for learning and memory. The main subject of this research project, GKAP, is implicated for number of neurological diseases including autism, schizophrenia, and obsessive-compulsive disorder. Thus, studying the function of GKAP in synaptic plasticity not only help understanding the higher cognitive function of human but also is directly relevant to disease.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Asanuma, Chiiko
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Medical College of Wisconsin
Schools of Medicine
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Danielson, Eric; Lee, Sang H (2014) SynPAnal: software for rapid quantification of the density and intensity of protein puncta from fluorescence microscopy images of neurons. PLoS One 9:e115298
Danielson, Eric; Metallo, Jacob; Lee, Sang H (2012) Role of TARP interaction in S-SCAM-mediated regulation of AMPA receptors. Channels (Austin) 6:393-7
Shin, Seung Min; Zhang, Nanyan; Hansen, Jonathan et al. (2012) GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling. Nat Neurosci 15:1655-66
Danielson, Eric; Zhang, Nanyan; Metallo, Jacob et al. (2012) S-SCAM/MAGI-2 is an essential synaptic scaffolding molecule for the GluA2-containing maintenance pool of AMPA receptors. J Neurosci 32:6967-80