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

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)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 ASDs4–7, non-syndromic intellectual disability8, and schizophrenia9. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients10, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem cells (iPSCs) 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 excitatory synapses that lack Shank3 but contain PSD95 and 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.

Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome

“…It is worth noting that the results we obtained for anxiety and social measurements from untreated Mecp2 mutant mice are very similar to those obtained in a PSD95 mutant mouse model, emphasizing the convergence of signaling pathways and synaptic molecules necessary for these behavioral functions (47). Indeed, IGF1 treatment improves excitatory synaptic transmission and motor behaviors in Shank3 haploinsufficient mice (48), and IGF1 application corrects synaptic transmission deficits in iPSC-derived neurons from 22q13 deletion syndrome patients (49), both of which can be attributed to enhanced PSD95 function.…”

Modeling Williams syndrome with induced pluripotent stem cells

“…23,25,29,30 Although the findings of the differences in the number of dendritic segments, branching points and trees did not agree between the iPSC model and postmortem tissue, we did observed a similar trend for WS iPSC-derived neurons to have a higher number of dendritic segments and branching points, as observed in WS postmortem brains. It is possible that iPSC-derived neurons lack the dynamics from environmental inputs, and deficiencies in dendritic segments and branching points may occur later in development, resulting in the only partial dendritic changes observed in postmortem specimens.…”

Phelan–McDermid Syndrome and SHANK3: Implications for Treatment

“…The structural synaptic changes resulted in reduced responses to AMPA-and NMDA-mediated electrical stimuli, and an overall imbalance of excitatory and inhibitory neuronal response [35]. Thus, it can be concluded that loss of SHANK3 results in detrimental effects on proper central nervous system (CNS) development and impaired synaptic transmission in both rodent and human neuronal models of PMS.…”

“…Using induced pluripotent stem cells from patients with PMS, Shcheglovitov et al [35] found significantly reduced levels of SHANK3 mRNA and protein expression, a faster rate of NMDA receptor decay, and an overall decrease in the number of AMPA and NMDA receptors. The structural synaptic changes resulted in reduced responses to AMPA-and NMDA-mediated electrical stimuli, and an overall imbalance of excitatory and inhibitory neuronal response [35].…”