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Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism |
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| Authors: | Bangash M Ali Park Joo Min Melnikova Tatiana Wang Dehua Jeon Soo Kyeong Lee Deidre Syeda Sbaa Kim Juno Kouser Mehreen Schwartz Joshua Cui Yiyuan Zhao Xia Speed Haley E Kee Sara E Tu Jian Cheng Hu Jia-Hua Petralia Ronald S Linden David J Powell Craig M Savonenko Alena Xiao Bo Worley Paul F |
| Affiliation: | 1 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 2 Departments of Pathology and Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 3 Departments of Neurology and Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8813, USA 4 The State Key Laboratory of Bio-Therapy, West China Hospital, Sichuan University, Chengdu 610065, China 5 Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA |
| 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. |
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