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Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model

Author

Listed:
  • Ferzin Sethna

    (Genetics Program, Michigan State University)

  • Wei Feng

    (Emory University School of Medicine)

  • Qi Ding

    (Michigan State University)

  • Alfred J. Robison

    (Michigan State University
    Neuroscience Program, Michigan State University)

  • Yue Feng

    (Emory University School of Medicine)

  • Hongbing Wang

    (Michigan State University
    Neuroscience Program, Michigan State University)

Abstract

Fragile X syndrome (FXS), caused by the loss of functional FMRP, is a leading cause of autism. Neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, we identify that, in Fmr1 knockout neurons, type 1 adenylyl cyclase (Adcy1) mRNA translation is enhanced, leading to excessive production of ADCY1 protein and insensitivity to neuronal stimulation. Genetic reduction of Adcy1 normalizes the aberrant ERK1/2- and PI3K-mediated signalling, attenuates excessive protein synthesis and corrects dendritic spine abnormality in Fmr1 knockout mice. Genetic reduction of Adcy1 also ameliorates autism-related symptoms including repetitive behaviour, defective social interaction and audiogenic seizures. Moreover, peripheral administration of NB001, an experimental compound that preferentially suppresses ADCY1 activity over other ADCY subtypes, attenuates the behavioural abnormalities in Fmr1 knockout mice. These results demonstrate a connection between the elevated Adcy1 translation and abnormal ERK1/2 signalling and behavioural symptoms in FXS.

Suggested Citation

  • Ferzin Sethna & Wei Feng & Qi Ding & Alfred J. Robison & Yue Feng & Hongbing Wang, 2017. "Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model," Nature Communications, Nature, vol. 8(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14359
    DOI: 10.1038/ncomms14359
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    1. Liang Yong & Yafen Yu & Bao Li & Huiyao Ge & Qi Zhen & Yiwen Mao & Yanxia Yu & Lu Cao & Ruixue Zhang & Zhuo Li & Yirui Wang & Wencheng Fan & Chang Zhang & Daiyue Wang & Sihan Luo & Yuanming Bai & Shir, 2022. "Calcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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