Early Adolescent Rai1 Reactivation Reverses Transcriptional and Social Interaction Deficits in a Mouse Model of Smith-Magenis Syndrome

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Oct 3

PMID 30275311

Citations 13

Authors

Wei-Hsiang Huang

David C Wang

William E Allen

Matthew Klope

Hailan Hu

Mehrdad Shamloo

Liqun Luo

Affiliations

Soon will be listed here.

Abstract

Haploinsufficiency of () 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 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 haploinsufficiency. In contrast, 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 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 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.

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