title: Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model.
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.
authors.affiliation: Genetics Program, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Ferzin
authors.initials: F
authors.lastname: Sethna
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA.|Neuroscience Program, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Alfred J
authors.initials: AJ
authors.lastname: Robison
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan 48824, USA.|Neuroscience Program, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D012640:Seizures / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000255:Adenosine Triphosphate; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases; D051860:Fragile X Messenger Ribonucleoprotein 1; C557530:5-((2-(6-Amino-9H-purin-9-yl) ethyl) amino)-1-pentanol; C497684:Fmr1 protein, mouse; C106670:adenylyl cyclase 1