TY - JOUR
T1 - Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3
AU - Wang, Xiaoming
AU - McCoy, Portia A.
AU - Rodriguiz, Ramona M.
AU - Pan, Yanzhen
AU - Je, H. Shawn
AU - Roberts, Adam C.
AU - Kim, Caroline J.
AU - Berrios, Janet
AU - Colvin, Jennifer S.
AU - Bousquet-Moore, Danielle
AU - Lorenzo, Isabel
AU - Wu, Gangyi
AU - Weinberg, Richard J.
AU - Ehlers, Michael D.
AU - Philpot, Benjamin D.
AU - Beaudet, Arthur L.
AU - Wetsel, William C.
AU - Jiang, Yong Hui
PY - 2011/8
Y1 - 2011/8
N2 - SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan-McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4-9. Isoform-specific Shank3 e4-9 homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3 e4-9 male mice display more severe impairments than females in motor coordination. Shank3 e4-9 mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3 e4-9 mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.
AB - SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan-McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4-9. Isoform-specific Shank3 e4-9 homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3 e4-9 male mice display more severe impairments than females in motor coordination. Shank3 e4-9 mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3 e4-9 mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.
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U2 - 10.1093/hmg/ddr212
DO - 10.1093/hmg/ddr212
M3 - Article
C2 - 21558424
AN - SCOPUS:79960111638
SN - 0964-6906
VL - 20
SP - 3093
EP - 3108
JO - Human molecular genetics
JF - Human molecular genetics
IS - 15
M1 - ddr212
ER -