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Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.

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.

Pubmed ID: 21565394

Authors

  • Bangash MA
  • Park JM
  • Melnikova T
  • Wang D
  • Jeon SK
  • Lee D
  • Syeda S
  • Kim J
  • Kouser M
  • Schwartz J
  • Cui Y
  • Zhao X
  • Speed HE
  • Kee SE
  • Tu JC
  • Hu JH
  • Petralia RS
  • Linden DJ
  • Powell CM
  • Savonenko A
  • Xiao B
  • Worley PF

Journal

Cell

Publication Data

May 27, 2011

Associated Grants

  • Agency: NIMH NIH HHS, Id: 5P50MH084020-03
  • Agency: NINDS NIH HHS, Id: 5R01NS070301-02
  • Agency: Autism Speaks, Id: AS7098
  • Agency: NICHD NIH HHS, Id: R01 HD069560
  • Agency: NICHD NIH HHS, Id: R01 HD069560-01
  • Agency: NICHD NIH HHS, Id: R01 HD069560-02
  • Agency: NIMH NIH HHS, Id: R01 MH081164
  • Agency: NINDS NIH HHS, Id: R01 NS070301
  • Agency: NINDS NIH HHS, Id: R01 NS070301-01
  • Agency: NINDS NIH HHS, Id: R01 NS070301-02
  • Agency: NIMH NIH HHS, Id: R01MH081164
  • Agency: NICHD NIH HHS, Id: R21 HD065290
  • Agency: NICHD NIH HHS, Id: R21 HD065290-01
  • Agency: NICHD NIH HHS, Id: R21 HD065290-02
  • Agency: NICHD NIH HHS, Id: R21HD065290

Mesh Terms

  • Animals
  • Autistic Disorder
  • Carrier Proteins
  • Disease Models, Animal
  • Hippocampus
  • Humans
  • Interpersonal Relations
  • Long-Term Potentiation
  • Long-Term Synaptic Depression
  • Mice
  • Nerve Tissue Proteins
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • Synapses
  • Ubiquitination