Visualization and correction of social abnormalities-associated neural ensembles in adult MECP2 duplication mice
Authors: Ruiguo Chen
Fuqiang Xu
Kunzhang Lin
Bo Yuan
Long Li
Tian-Lin Cheng
Qian Wu
Kun Song
Na Pan
Xiaobin He
Le Sun
Zilong Qiu
Xiaoqun Wang
Shiyang Chang
Journal: Science Bulletin (2020)
Discipline: Multidisciplinary
Keywords: Autism; CRISPR/Cas9; In vivo calcium imaging; MECP2; Social activity.

Abstract:  Duplications of MECP2-containing genomic segments led to severe autistic symptoms in male. Transgenic mice overexpressing the human MECP2 gene exhibit autistic-like behaviors. Neural circuits underlying social defects in MECP2 transgenic (MECP2-TG) mice remain unknown. To observe neural activity of MECP2-TG mice in vivo, we performed calcium imaging by implantation of microendoscope in the hippocampal CA1 regions of MECP2-TG and wild type (WT) mice. We identified neurons whose activities were tightly associated with social interaction, which activity patterns were compromised in MECP2-TG mice. Strikingly, we rescued the social-related neural activity in CA1 and social defects in MECP2-TG mice by deleting the human MECP2 transgene using the CRISPR/Cas9 method during adulthood. Our data points to the neural circuitry responsible for social interactions and provides potential therapeutic targets for autism in adulthood. 

Retracted: No

PubPeer comments:
 In the present paper, the authors used the FVB-Tg(MECP2)1Hzo J (Strain 008679) generated by the Zoghbi lab and first documented by Collins et al. in 2004 in *Hum Mol Genet* . Unfortunately, the FVB mice are notorious for developing retinal degeneration by the wean age, which can obviously confound the interpretation of behavioral tests of the present study. The Jackson Laboratories clearly states that the FVB  are homozygous for the retinal degeneration 1 allele of *Pde6brd1*, resulting in blindness by wean age.  in the description of the mice: https: www.jax.org strain 001800 and I believe that by now all labs from the Rett MeCP2 field are fully aware of the caveat. In addition, several studies from the Zoghbi lab published after the 2004 paper clearly warn the reader about the caveat of using the MeCP2 TG from the FVB background and advise to use instead F1 hybrids from FVB x C57BL6 crossings. Please find here some selected example: Samaco et al., 2012 *Nat Genet* https: www.ncbi.nlm.nih.gov pmc articles PMC3267865 and Sztainberg et al., 2015 *Nature* https: www.ncbi.nlm.nih.gov pmc articles PMC4839300 In the current situation I believe that the interpretations of the paper are severely affected and hope that both the scientific community and the Editors at *Science Bulletin* will make the necessary to address the issue. Since, the information about the problem of using the FVB-MeCP2 TG line is not new and discussed widely including in papers cited by the authors..one could have hoped that the reviewers or editors would flag this issue. Best regards, , 
 we thank you for this kind comment. we have been working on this FVB background MECP2 overexpression mice for years. although there are reports showing visual problems with FVB mice, we did observe robust social defects in FVB background MECP2 overexpression mice, as we also published behavioral deficits of FVB MECP2 tg mice in great details in an other paper coming out this year . if you are not familiar with what kinds of the behavioral abnormalities FVB MECP2 transgenic mice may have. you are welcome to take a deeper look. , 
 Dear Prof. Qiu, Thank you for the prompt reply! I understand and agree that the impact of MeCP2 duplication is such that one could observe behavioral abnormalities, even in mice suffering from retinal degeneration. That being said, I would respectfully submit here that studying social interaction (or any other behavior) on potentially blind mice does not represent the most sensible approach. I am working with MeCP2 models (both KO and TG) and as many of my peers in the field I would argue that FVB x BL6 F1 hybrids are *de facto* better to study such behaviors as it would help you to rule out any confounding effects due to the rd1 mutation. Interestingly, you studied these F1 hybrids in the *Neurosci. Bull.* paper you now mention in your answer. Thus I find very unfortunate that you did not include these animals in the *Science Bulletin* study. I could only advise you to either add a correction to the paper to make this point clearer to ensure that the reader will not be misled in his interpretations or to include such comparison in your future investigations. Best regards. ,