Neuronal impairment and treatment prospects in Smith Magenis syndrome: Findings from patient-specific neuronal model

Smith Magenis syndrome (SMS) is a rare neurodevelopmental disorder resulting from a microdeletion on chromosomal region 17p11.2, which includes the Retinoic acid-induced 1 (RAI1) gene. Individuals with SMS exhibit a spectrum of psychiatric and neurological manifestations, such as developmental delays, behavioral disturbances, an intellectual disability (ID), and a circadian disorder. Additionally, they may present symptoms typical of Parkinsonism. Despite the availability of rodent models for SMS, the lack of cellular models and potential treatments has limited an in-depth study. In this research, patient-derived hippocampal and dopaminergic neurons were generated from induced pluripotent stem cells (iPSCs) to investigate electrophysiological properties, synaptic activity, and differential gene expression. Furthermore, the impact of a retinoic acid derivatives on the electrophysiological properties of the hippocampal neurons derived from SMS patients was also explored. The results revealed a hypoexcitability and reduced synaptic activity in patient-derived hippocampal as well as dopaminergic neurons compared to the isogenic control line at 6-7 weeks post-differentiation. Notably, chronic administration of the drug led to a significant improvement in the phenotypes and increased neuronal survival, holding potential implications for treatment.