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Author (up) Shcheglovitov, A.; Shcheglovitova, O.; Yazawa, M.; Portmann, T.; Shu, R.; Sebastiano, V.; Krawisz, A.; Froehlich, W.; Bernstein, J.A.; Hallmayer, J.F.; Dolmetsch, R.E. url  doi
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  Title SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients Type Journal Article
  Year 2013 Publication Nature Abbreviated Journal Nature  
  Volume 503 Issue 7475 Pages 267-271  
  Keywords Cell Line; Child; Chromosome Deletion; Chromosome Disorders/genetics/*physiopathology; Chromosomes, Human, Pair 22/genetics; Female; GABA Agents/pharmacology; Gene Expression Regulation/drug effects; Humans; Insulin-Like Growth Factor I/*pharmacology; Lentivirus/genetics; Male; Nerve Tissue Proteins/*genetics/*metabolism; Neurons/cytology/drug effects/*physiology; Pluripotent Stem Cells/cytology; Receptors, Glutamate/genetics; Sequence Deletion; Synapses/*drug effects/genetics/*physiology; Synaptic Transmission/drug effects/genetics  
  Abstract Phelan-McDermid syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of autism spectrum disorders (ASDs). PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N-methyl-D-aspartate (NMDA) receptors with fast deactivation kinetics. Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it.  
  Address Department of Neurobiology, Stanford University, Stanford, California 94305, USA  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:24132240 Approved no  
  Call Number refbase @ user @ Serial 16867  
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