title: Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism.
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.
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: M Ali
authors.initials: MA
authors.lastname: Bangash
authors.forename: Joo Min
authors.initials: JM
authors.lastname: Park
authors.forename: Tatiana
authors.initials: T
authors.lastname: Melnikova
authors.forename: Dehua
authors.initials: D
authors.lastname: Wang
authors.forename: Soo Kyeong
authors.initials: SK
authors.lastname: Jeon
authors.forename: Deidre
authors.initials: D
authors.lastname: Lee
authors.forename: Sbaa
authors.initials: S
authors.lastname: Syeda
authors.forename: Juno
authors.initials: J
authors.lastname: Kim
authors.forename: Mehreen
authors.initials: M
authors.lastname: Kouser
authors.forename: Joshua
authors.initials: J
authors.lastname: Schwartz
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Cui
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Haley E
authors.initials: HE
authors.lastname: Speed
authors.forename: Sara E
authors.initials: SE
authors.lastname: Kee
authors.forename: Jian Cheng
authors.initials: JC
authors.lastname: Tu
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Hu
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.forename: David J
authors.initials: DJ
authors.lastname: Linden
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
authors.forename: Alena
authors.initials: A
authors.lastname: Savonenko
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007398:Interpersonal Relations; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D051379:Mice; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D008840:Microfilament Proteins; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C492356:Shank3 protein, mouse