Microdeletion of 22q13 region encompassing SHANK3 gene and rare heterozygous mutations in SHANK3 have been associated with neurodevelopmental disorder Phelan–McDermid syndrome (PMDS), autism spectrum disorders (ASDs), non-syndromic intellectual disability, and schizophrenia. However, the cellular and molecular phenotypes resulting from SHANK3 haploinsufficiency in human neurons are unknown. In this study, induced pluripotent stem (iPS) cells were generated from individuals with PMDS and autism to produce functional neurons. PMDS neurons were found to 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. These 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.

http://www.nature.com/nature/journal/v503/n7475/full/nature12618.html#affil-auth

Posted by Nicola Brunetti-Pierri, MD, FACMG