17888
IGF1 restore synaptic deficits in neurons from Phelan-McDermid syndrome patients
Friday, May 16, 2014: 2:45 PM
Marquis D (Marriott Marquis Atlanta)
O. Shcheglovitov1, O. Shcheglovitova1, M. Yazawa1, T. Portmann1, R. Shu1, V. Sebastiano2, A. Krawisz1, W. Froehlich3, J. A. Bernstein4, J. F. Hallmayer5 and R. Dolmetsch6, (1)Neurobiology, Stanford University School of Medicine, Stanford, CA, (2)Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, (3)Child and Adolescent Child Psychiatry, Stanford University School of Medicine, Stanford, CA, (4)Pediatrics, Stanford University, Stanford, CA, (5)Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, (6)Novartis Institutes for Biomedical Research, Cambridge, MA
Background: 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.
Objectives: To investigate cellular and molecular phenotypes associated with PMDS in human neurons.
Methods: We generated induced pluripotent stem cells (iPSCs) from individuals with PMDS and autism and used them to produce functional neurons. We then use elctrophysiology, biochemistry, and molecular biology to characterize the properties of iPSC-derived neurons.
Results: 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 excitatory synapses that lack Shank3 but contain PSD95 and NMDA receptors with fast deactivation kinetics.
Conclusions: 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.
