SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients

• Published in: Nature (London) 2013-11, Vol.503 (7475), p.267-271
• Main Authors: Shcheglovitov, Aleksandr, Shcheglovitova, Olesya, Yazawa, Masayuki, Portmann, Thomas, Shu, Rui, Sebastiano, Vittorio, Krawisz, Anna, Froehlich, Wendy, Bernstein, Jonathan A., Hallmayer, Joachim F., Dolmetsch, Ricardo E.
• Format: Article
• Language: English
• Subjects: 631/378/1689/1373; Acids; Analysis; Biological and medical sciences; Cell Line; Child; Chromosome Deletion; Chromosome Disorders - genetics; Chromosome Disorders - physiopathology; Chromosomes, Human, Pair 22 - genetics; Defects; Female; Fundamental and applied biological sciences. Psychology; GABA Agents - pharmacology; Gene expression; Gene Expression Regulation - drug effects; Genotype & phenotype; Humanities and Social Sciences; Humans; Insulin-Like Growth Factor I - pharmacology; Lentivirus - genetics; letter; Male; Medical research; Medicine, Experimental; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural transmission; Neurological research; Neurology; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Neurophysiology; Phelan-McDermid syndrome; Physiological aspects; Pluripotent Stem Cells - cytology; Proteins; Receptors, Glutamate - genetics; Rodents; Science; Sequence Deletion; Stem cells; Synapses - drug effects; Synapses - genetics; Synapses - physiology; Synaptic Transmission - drug effects; Synaptic Transmission - genetics; Vertebrates: nervous system and sense organs
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12618

Deletions of chromosome 22q13.3 cause Phelan–McDermid syndrome (PMDS), a neurodevelopmental disorder associated with autism; here induced pluripotent stem cells from PMDS patients with autism are used to produce neurons, they are shown to have reduced SHANK3 expression and a defect in excitatory synaptic transmission which can be restored either by increasing SHANK3 or with insulin-like growth factor 1. The nature of Phelan–McDermid syndrome Deletions of chromosome 22q13.3 cause Phelan–McDermid syndrome (PMDS), a neurodevelopmental disorder associated with autism. Ricardo Dolmetsch and colleagues generated induced pluripotent stem (iPS) cells from PMDS patients with autism and used them to produce neurons. PMDS neurons have reduced expression of the SHANK3 gene, which encodes a protein found in a structure known as the postsynaptic density, and a defect in excitatory synaptic transmission that can be restored either by increasing SHANK3 or with insulin-like growth factor 1. These findings add to the picture of synaptic deficits observed in autism spectrum disorders, and point to potential mechanisms for restoring them. 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) 1 . 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) 2 , 3 . Rare mutations in SHANK3 have been associated with idiopathic ASDs 4 , 5 , 6 , 7 , non-syndromic intellectual disability 8 , and schizophrenia 9 . Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients 10 , 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 d