Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith-Magenis syndrome

Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):10744-10749. doi: 10.1073/pnas.1806796115. Epub 2018 Oct 1.


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.

Keywords: Smith–Magenis syndrome; autism spectrum disorders; chromatin; copy number variation; social behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Disease Models, Animal*
  • Haploinsufficiency*
  • Heterozygote
  • Humans
  • Interpersonal Relations*
  • Male
  • Mice
  • Mutation
  • Phenotype
  • Smith-Magenis Syndrome / genetics*
  • Smith-Magenis Syndrome / pathology
  • Social Behavior Disorders / genetics
  • Social Behavior Disorders / prevention & control*
  • Trans-Activators / pharmacology*


  • Rai1 protein, mouse
  • Trans-Activators