Enhanced polyubiquitination of shank3 and NMDA receptor in a mouse model of autism

M. Ali Bangash, Joo Min Park, Tatiana Melnikova, Dehua Wang, Soo Kyeong Jeon, Deidre Lee, Sbaa Syeda, Juno Kim, Mehreen Kouser, Joshua Schwartz, Yiyuan Cui, Xia Zhao, Haley E. Speed, Sara E. Kee, Jian Cheng Tu, Jia Hua Hu, Ronald S. Petralia, David J. Linden, Craig M. Powell, Alena SavonenkoBo Xiao, Paul F. Worley

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Abstract

We have created a mouse genetic model that mimics a human mutation of Shank3 that deletes the C terminus and is associated with autism. Expressed as a single copy [Shank3(+/ΔC) mice], Shank3ΔC protein interacts with the wild-type (WT) gene product and results in >90% reduction of Shank3 at synapses. This "gain-of-function" phenotype is linked to increased polyubiquitination of WT Shank3 and its redistribution into proteasomes. Similarly, the NR1 subunit of the NMDA receptor is reduced at synapses with increased polyubiquitination. Assays of postsynaptic density proteins, spine morphology, and synapse number are unchanged in Shank3(+/ΔC) mice, but the amplitude of NMDAR responses is reduced together with reduced NMDAR-dependent LTP and LTD. Reciprocally, mGluR-dependent LTD is markedly enhanced. Shank3(+/ΔC) mice show behavioral deficits suggestive of autism and reduced NMDA receptor function. These studies reveal a mechanism distinct from haploinsufficiency by which mutations of Shank3 can evoke an autism-like disorder.

Original languageEnglish (US)
Pages (from-to)758-772
Number of pages15
JournalCell
Volume145
Issue number5
DOIs
StatePublished - May 27 2011

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bangash, M. A., Park, J. M., Melnikova, T., Wang, D., Jeon, S. K., Lee, D., Syeda, S., Kim, J., Kouser, M., Schwartz, J., Cui, Y., Zhao, X., Speed, H. E., Kee, S. E., Tu, J. C., Hu, J. H., Petralia, R. S., Linden, D. J., Powell, C. M., ... Worley, P. F. (2011). Enhanced polyubiquitination of shank3 and NMDA receptor in a mouse model of autism. Cell, 145(5), 758-772. https://doi.org/10.1016/j.cell.2011.03.052