LAUSR

Significance Losing one copy of the RAI1 gene causes Smith–Magenis syndrome (SMS), a neurodevelopmental disorder. Using a newly generated SMS mouse model, this study demonstrates that restoring the Rai1 gene dose in an early postnatal window could repair gene expression and social interaction deficits in this SMS model. The SMS mouse model also showed a reduced density of dendritic spines, anatomical correlates of excitatory synapses, in the prefrontal cortex. Artificial activation of prefrontal cortex neurons partially alleviated the behavioral deficits. These findings suggest that, similar to Rett syndrome, SMS is caused by disruption of a chromatin-modifying gene with reversible developmental phenotypes, highlighting the potential treatment windows in childhood or adolescence. Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith–Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3–4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.