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

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Early Adolescent Rai1 Reactivation Reverses Transcriptional and Social Interaction Deficits in a Mouse Model of Smith–Magenis Syndrome Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith–Magenis syndrome Wei-Hsiang Huanga,b,1, David C. Wanga,b, William E. Allena,c, Matthew Kloped, Hailan Hue,f, Mehrdad Shamlood,g, and Liqun Luoa,b,c,1 aHoward Hughes Medical Institute, Stanford University, Stanford, CA 94305; bDepartment of Biology, Stanford University, Stanford, CA 94305; cNeurosciences Program, Stanford University, Stanford, CA 94305; dStanford Behavioral and Functional Neuroscience Laboratory, Stanford University School of Medicine, Stanford, CA 94305; eInterdisciplinary Institute of Neuroscience and Technology, Zhejiang University, 310012 Hangzhou, People’s Republic of China; fQiushi Academy for Advanced Studies, Zhejiang University, 310012 Hangzhou, People’s Republic of China; and gDepartment of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305 Contributed by Liqun Luo, August 24, 2018 (sent for review April 20, 2018; reviewed by Guoping Feng and Daniel H. Geschwind) Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith– sensitive to RAI1 dosage. Currently, no cure is available for SMS Magenis syndrome (SMS), a syndromic autism spectrum disorder or PTLS patients. Treatments of symptoms with neuroleptics, associated with craniofacial abnormalities, intellectual disability, antipsychotics, and serotonin reuptake inhibitors demonstrate and behavioral problems. There is currently no cure for SMS. Here, limited success at the cost of significant adverse effects (10, 11). we generated a genetic mouse model to determine the reversibil- Rai1 encodes a chromatin-binding protein that regulates the ex- ity of SMS-like neurobehavioral phenotypes in Rai1 heterozygous pression of many neurodevelopmental genes in the mammalian mice. We show that normalizing the Rai1 level 3–4 wk after birth brain (12). It is thus difficult to develop a therapeutic strategy that corrected the expression of genes related to neural developmental simultaneously targets multiple Rai1 downstream pathways. In mice, pathways and fully reversed a social interaction deficit caused by Rai1 begins to express at embryonic day 9.5 and is continuously − − Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after expressed throughout adulthood (12, 13). Most Rai1 / mice die as birth was not beneficial. We also demonstrated that the correct embryos (13), demonstrating that Rai1 is essential during early Rai1 dose is required in both excitatory and inhibitory neurons for embryonic development. Therefore, it is possible that SMS symp- proper social interactions. Finally, we found that Rai1 heterozy- toms are a consequence of irreversible damage to neural functions gous mice exhibited a reduction of dendritic spines in the medial resulting from the absence of Rai1 during early development. prefrontal cortex (mPFC) and that optogenetic activation of mPFC However, Rai1 is continuously expressed in the adult brain (12), neurons in adults improved the social interaction deficit of Rai1 suggesting that Rai1 function may also be required beyond devel- heterozygous mice. Together, these results suggest the existence opment. If true, it is possible that postnatal restoration of a normal of a postnatal temporal window during which restoring Rai1 can Rai1 expression level may improve neural functions and reverse improve the transcriptional and social behavioral deficits in a SMS symptoms. To distinguish between these possibilities, we mouse model of SMS. It is possible that circuit-level interventions combined genetic- and circuit-level interventions to correct SMS- would be beneficial beyond this critical window. like transcriptional and neurobehavioral phenotypes in mice. autism spectrum disorders | copy number variation | chromatin | social Significance behavior | Smith–Magenis syndrome Losing one copy of the RAI1 gene causes Smith–Magenis syn- enomic disorders are common conditions (1 in 1,000 births) drome (SMS), a neurodevelopmental disorder. Using a newly Gcaused by chromosomal instability and copy number varia- generated SMS mouse model, this study demonstrates that tion that result in structural variations of DNA fragments (1). restoring the Rai1 gene dose in an early postnatal window While the pathology is often driven by dosage imbalance of could repair gene expression and social interaction deficits in multiple genes, sometimes a single dosage-sensitive gene is re- this SMS model. The SMS mouse model also showed a reduced sponsible for the majority of phenotypes (1). One such example is density of dendritic spines, anatomical correlates of excitatory Smith–Magenis syndrome (SMS), a neurodevelopmental disorder synapses, in the prefrontal cortex. Artificial activation of pre- frequently diagnosed in infancy or early childhood due to hypo- frontal cortex neurons partially alleviated the behavioral defi- tonia and dysmorphic features (2). With age, SMS patients display cits. These findings suggest that, similar to Rett syndrome, SMS neurological features including cognitive impairment, self- is caused by disruption of a chromatin-modifying gene with injurious behaviors, and stereotypies (2). Most SMS patients reversible developmental phenotypes, highlighting the po- (>90%) meet criteria for autism spectrum disorder (ASD) at tential treatment windows in childhood or adolescence. some point in their lives (3). Ninety percent of SMS patients harbor chromosomal deletions in 17p11.2 (4), while the remaining Author contributions: W.-H.H., H.H., and L.L. designed research; W.-H.H., D.C.W., and 10% have point mutations or small deletions in Retinoic Acid M.K. performed research; W.-H.H. contributed new reagents/analytic tools; W.-H.H., D.C.W., W.E.A., M.K., M.S., and L.L. analyzed data; and W.-H.H. and L.L. wrote the paper. Induced 1 (RAI1), which resides in 17p11.2 (4, 5). Phenotypic Reviewers: G.F., Massachusetts Institute of Technology; and D.H.G., University of Califor- comparison between patients with 17p11.2 deletions and RAI1 nia, Los Angeles. mutations demonstrated that most SMS features are a result of The authors declare no conflict of interest. RAI1 haploinsufficiency (6). Importantly, an increased RAI1 level – This open access article is distributed under Creative Commons Attribution-NonCommercial- may contribute to Potocki Lupski syndrome (PTLS), a neuro- NoDerivatives License 4.0 (CC BY-NC-ND). developmental disorder characterized by 17p11.2 duplication and 1To whom correspondence may be addressed. Email: [email protected] or lluo@ high prevalence of ASD (>60%) (7, 8). Although RAI1 is among stanford.edu. the dozens of genes overexpressed in PTLS, the smallest region This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. common to PTLS patients with different duplications is a 125-kb 1073/pnas.1806796115/-/DCSupplemental. region containing only RAI1 (9). Therefore, the nervous system is Published online October 1, 2018. 10744–10749 | PNAS | October 16, 2018 | vol. 115 | no. 42 www.pnas.org/cgi/doi/10.1073/pnas.1806796115 Downloaded by guest on October 2, 2021 + Results male Rai1STOP/ mice and their wild-type (WT) littermates to An SMS Mouse Model That Allows Conditional Reactivation. To test examine their neural functions. STOP/+ reversibility of SMS in mice, we generated a knock-in Rai1 allele In the activity chamber, Rai1 mice showed an increased (Rai1STOP) with an insertion of a loxP-flanked transcriptional stereotypical vertical activity (rearing) (Fig. 1D) while retaining an stop cassette before the start codon, which should prevent the otherwise normal activity level (Fig. 1E). The time spent in the expression of any Rai1 protein before Cre-mediated re- periphery and center of the activity chamber was not different STOP/+ combination (Fig. 1A and SI Appendix, Fig. S1A). We found that, between Rai1 and WT mice (SI Appendix,Fig.S1B and C), − − + similar to Rai1 / mice (13), most Rai1STOP/STOP mice died in suggesting a normal anxiety level. Rai1STOP/ mice showed normal utero (91%, n = 175), suggesting that Rai1STOP functions as a motor coordination in the pole test and normal context- and cued- null allele in the absence of Cre activity. Quantitative RT-PCR recalls in the fear-conditioning test (SI Appendix,Fig.S1D and E). and Western blot confirmed that the stop cassette effectively Furthermore, they retained normal spatial learning as shown by Y inhibited the expression of Rai1 (Fig. 1 B and C). We then maze and Morris water maze (SI Appendix,Fig.S1F–H). A hot STOP/+ performed a battery of behavioral assays using 8- to 10-wk-old plate test showed that Rai1 mice retained normal pain sensitivity (SI Appendix,Fig.S1I). These results are consistent with + − previous findings in Rai1 / mice (12, 14). One cardinal feature of ASD is abnormal reciprocal social A E Distance moved interaction (15, 16). We used a tube test to measure social in- teraction by quantifying the encounters between two unfamiliar 1500 WT mice (17). When two mice are simultaneously released from Rai1STOP/+ 1000 opposing ends of a transparent tube, one mouse will eventually be pushed out or voluntarily retreat from the tube and be de- 500 clared as the “loser” (SI Appendix, Fig. S1J). When performed on 0 mice that share a cage, the tube test measures social hierarchy Distance Moved (cm) 0510 and dominance (18, 19). For unfamiliar mice that have not Time (min) B established social hierarchy, as in our case, the tube test reflects Velocity the willingness of stranger mice to maintain
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