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 (10 mg/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 (0.3–1.0 mg/kg i.p.). The pattern of behavioural abnormalities in 667-COUMATE-treated mice implicated a genetic substrate at 21–23 cM 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 (1.0 mg/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.
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DHEA
Trevor Humby,a,b,c Ellen S. Cross,b Lauren Messer,a Silvia Guerrero,d and William Daviesa,b,c,⁎
Author Information
a School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK
b Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
c 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
d University of Barcelona, Gran Via de les Corts Catalanes, 585 08007 Barcelona, Spain
Trevor Humby: ku.ca.ffidrac@tybmuh; Ellen S. Cross: ku.ca.ffidrac@SEssorC; Lauren Messer: moc.liamg@49ressemnerual; Silvia Guerrero: moc.liamtoh@2i2_aivlis; William Davies: ku.ca.ffidrac@4wseivad
⁎ Corresponding author at: Cardiff University School of Psychology, 70, Park Place, Cardiff CF10 3AT, UK.School of PsychologyCardiff UniversityTower Building70, Park PlaceCardiffCF10 3ATUK
Psychoneuroendocrinology. 2016 Dec; 74: 363–370. doi: 10.1016/j.psyneuen.2016.09.019 PMCID: PMC5094271
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094271/
by Oleg Vishnevski | Dec 3, 2016