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NMDA receptor-dependent regulation of dendritic spine morphology by SAP102 splice variants
Journal article   Open access   Peer reviewed

NMDA receptor-dependent regulation of dendritic spine morphology by SAP102 splice variants

Bo-Shiun Chen, Eleanor V Thomas, Antonio Sanz-Clemente and Katherine W Roche
The Journal of neuroscience, v 31(1), pp 89-96
05 Jan 2011
DOI: https://doi.org/10.1523/JNEUROSCI.1034-10.2011
PMID: 21209193
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
http://www.jneurosci.org/content/jneuro/31/1/89.full.pdfView
Published, Version of Record (VoR) Open
url
https://doi.org/10.1523/JNEUROSCI.1034-10.2011View
Published, Version of Record (VoR) Open

Abstract

Analysis of Variance Animals Cells, Cultured Dendritic Spines - drug effects Dendritic Spines - genetics Dendritic Spines - metabolism Embryo, Mammalian Excitatory Amino Acid Antagonists - pharmacology Gene Expression Regulation - genetics Green Fluorescent Proteins - genetics Hippocampus - cytology Humans In Vitro Techniques Microscopy, Confocal Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Neurons - drug effects Neurons - ultrastructure Neuropeptides - genetics Post-Synaptic Density - drug effects Post-Synaptic Density - genetics Protein Binding - drug effects Protein Binding - genetics Protein Isoforms - genetics Protein Transport - drug effects Protein Transport - genetics Rats Receptors, N-Methyl-D-Aspartate - genetics Receptors, N-Methyl-D-Aspartate - metabolism RNA, Small Interfering - metabolism Transfection - methods Two-Hybrid System Techniques Valine - analogs & derivatives Valine - pharmacology
Membrane-associated guanylate kinases (MAGUKs) are major components of the postsynaptic density and play important roles in synaptic organization and plasticity. Most excitatory synapses are located on dendritic spines, which are dynamic structures that undergo morphological changes during synapse formation and plasticity. Synapse-associated protein 102 (SAP102) is a MAGUK that is highly expressed early in development and mediates receptor trafficking during synaptogenesis. Mutations in human SAP102 cause mental retardation, which is often accompanied with abnormalities in dendritic spines. However, little is known about the role of SAP102 in regulating synapse formation or spine morphology. We now find that SAP102 contains a novel NMDA receptor binding site in the N-terminal domain, which is specific for the NR2B subunit. The interaction between SAP102 and NR2B is PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain independent and is regulated by alternative splicing of SAP102. We show that SAP102 that possesses an N-terminal insert is developmentally regulated at both mRNA and protein levels. In addition, expression of SAP102 increases synapse formation. Furthermore, the alternative splicing of SAP102 regulates dendritic spine morphology. SAP102 containing the N-terminal insert promotes lengthening of dendritic spines and preferentially promotes the formation of synapses at long spines, whereas a short hairpin RNA knockdown of the same SAP102 splice variant causes spine shrinkage. Finally, blocking NMDA receptor activity prevents the spine lengthening induced by the N-terminal splice variant of SAP102. Thus, our data provide the first evidence that SAP102 links NMDA receptor activation to alterations in spine morphology.

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Neurosciences
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