title: A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis.
abstract: Postpartum psychosis (PP) is a severe psychiatric disorder affecting a small proportion of new mothers shortly after childbirth. The molecular pathophysiology underlying the disorder is currently poorly understood, and there are no amenable animal models for the condition; maternal deficiency for the enzyme steroid sulfatase has been proposed as a potential risk mechanism. Here we show that inhibition of steroid sulfatase with 667-COUMATE (10mg/kg p.o.) in new mouse mothers results in behavioural abnormalities that can be partially alleviated by the administration of the clinically-efficacious antipsychotic ziprasidone (0.3-1.0mg/kg i.p.). The pattern of behavioural abnormalities in 667-COUMATE-treated mice implicated a genetic substrate at 21-23cM on chromosome 15; of the 17 genes within this chromosomal interval, only one (Nov/Ccn3) was significantly differentially expressed in the brains of vehicle and 667-COUMATE-treated mice. Two additional members of the Ccn family (Ccn2/Ctgf and Ccn4/Wisp1) were also significantly differentially expressed between the two groups, as were three further genes co-expressed with Nov/Ccn3 in brain (Arhgdig) or previously implicated in disorder risk by clinical studies (Adcy8 and Ccl2). The expression of Nov/Ccn3, but not of the other differentially-expressed genes, could be normalised by ziprasidone administration (1.0mg/kg). NOV/CCN3 lies directly under a linkage peak for PP risk at 8q24, and the associated protein possesses numerous characteristics that make it an excellent candidate mediator of PP risk. Our data suggest the 667-COUMATE-treated mouse as a model for PP with some degree of face, construct, and predictive validity, and implicate a novel, and biologically-plausible, molecular risk pathway for PP.
authors.affiliation: School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK. Electronic address: humbyt@cardiff.ac.uk.
authors.forename: Trevor
authors.initials: T
authors.lastname: Humby
authors.affiliation: Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK. Electronic address: CrossES@cardiff.ac.uk.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Cross
authors.affiliation: School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK. Electronic address: laurenmesser94@gmail.com.
authors.forename: Lauren
authors.initials: L
authors.lastname: Messer
authors.affiliation: University of Barcelona, Gran Via de les Corts Catalanes, 585 08007 Barcelona, Spain. Electronic address: silvia_2i2@hotmail.com.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guerrero
authors.affiliation: School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK. Electronic address: daviesw4@cardiff.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Davies
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003374:Coumarins / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011618:Psychotic Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D011644:Puerperal Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C100463:4-methylcoumarin 7-O-sulfamate; D014150:Antipsychotic Agents; D003374:Coumarins; D010879:Piperazines; D013449:Sulfonamides; D013844:Thiazoles; C092292:ziprasidone; D043266:Steryl-Sulfatase
keywords: 667-COUMATE; Elevated plus maze; Nephroblastoma-overexpressed; Startle response; Steroid sulfatase