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

Ferzin Sethna, Wei Feng, Qi Ding, Alfred J. Robison, Yue Feng and Hongbing Wang ()
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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
Yue Feng: Emory University School of Medicine
Hongbing Wang: Michigan State University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14359

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