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Structure and function of neonatal social communication in a genetic mouse model of autism

Molecular Psychiatry volume 21, pages 1208–1214 (2016)Cite this article

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Abstract

A critical step toward understanding autism spectrum disorder (ASD) is to identify both genetic and environmental risk factors. A number of rare copy number variants (CNVs) have emerged as robust genetic risk factors for ASD, but not all CNV carriers exhibit ASD and the severity of ASD symptoms varies among CNV carriers. Although evidence exists that various environmental factors modulate symptomatic severity, the precise mechanisms by which these factors determine the ultimate severity of ASD are still poorly understood. Here, using a mouse heterozygous for Tbx1 (a gene encoded in 22q11.2 CNV), we demonstrate that a genetically triggered neonatal phenotype in vocalization generates a negative environmental loop in pup–mother social communication. Wild-type pups used individually diverse sequences of simple and complicated call types, but heterozygous pups used individually invariable call sequences with less complicated call types. When played back, representative wild-type call sequences elicited maternal approach, but heterozygous call sequences were ineffective. When the representative wild-type call sequences were randomized, they were ineffective in eliciting vigorous maternal approach behavior. These data demonstrate that an ASD risk gene alters the neonatal call sequence of its carriers and this pup phenotype in turn diminishes maternal care through atypical social communication. Thus, an ASD risk gene induces, through atypical neonatal call sequences, less than optimal maternal care as a negative neonatal environmental factor.

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Acknowledgements

We thank Bernice Morrow for providing us with the original line of Tbx1 heterozygous breeders. This work was supported by the NIH (HD053114 and MH099660), a NARSAD Independent Investigator Award to NH and a Maltz Foundation award to NH, a Grant-in-Aid for Scientific Research on Innovative Areas (No. 4501) from the Japan Society for the Promotion of Science, in Japan to TK; MB and JLP were supported by the NIH award (DC007690).

Author contributions

TT, AN, SA and NH contributed to the overall design and execution of experiments and analyses. TT, SO, PÓB, AN, KY, MVB, JLP, AG, TK and NH wrote the manuscript. GK and AN recorded pup vocalization and annotated call types. TT, TI and AN constructed all data files that were used for analyses. KY applied PLS-DA analysis to the proportion of vocal call types. PÓB and AG determined the sequence structure of vocal calls using sPLS-DA and entropy analyses. MVB and JLP analyzed call sequences using Markov chains. SO, AM and TK conducted the maternal approach experiment.

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Author notes

  1. T Takahashi, S Okabe, P Ó Broin and A Nishi: These four authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA

    T Takahashi, A Nishi, T Izumi, G Kang, S Abe & N Hiroi

  2. Department of Animal Science and Biotechnology, Azabu University, Sagamihara, Kanagawa, Japan

    S Okabe, A Machida & T Kikusui

  3. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

    P Ó Broin, A Golden & N Hiroi

  4. Department of Psychiatry, Course of Integrated Brain Sciences and Medical Informatics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

    A Nishi

  5. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

    K Ye

  6. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA

    M V Beckert, J L Pena & N Hiroi

  7. Department of Neuropharmacology, Graduate School of Hokkaido University College of Medicine, Sapporo, Japan

    T Izumi

  8. Department of Mathematical Sciences, Yeshiva University, New York, NY, USA

    A Golden

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  1. T Takahashi
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Correspondence to N Hiroi.

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Takahashi, T., Okabe, S., Broin, P. et al. Structure and function of neonatal social communication in a genetic mouse model of autism. Mol Psychiatry 21, 1208–1214 (2016). https://doi.org/10.1038/mp.2015.190

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