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.
Highlights
Postpartum psychosis (PP) is a severe psychiatric disorder occurring shortly after childbirth in 1–2 out of every 1000 mothers (Sit et al, 2006)
Elevated plus-maze Treatment with 667-COUMATE in new mothers resulted in a significantly reduced latency to enter the open arms of the maze, and a significantly greater propensity towards rearing; these effects occurred in the absence of significant effects on other behavioural measures assessed in this test (Table 1)
We examined the expression of: a) murine orthologues of three genes suggested as positional candidates for PP (Jones et al, 2007) (Abat and Grin2a at 16p13, and Adcy8 at 8q24), b) two genes within 16p13 whose expression correlates with CTGF/CCN2 or NOV/CCN3 expression in developing human brain tissue (Li et al, 2016) (Hbaa1/a2 and Arhgdig), and c) two genes suggested by genomewide association studies as candidates for bipolar disorder (Cacna1c and Odz4/Tenm4)(Harrison, 2016)
Summary
Postpartum psychosis (PP) is a severe psychiatric disorder occurring shortly after childbirth in 1–2 out of every 1000 mothers (Sit et al, 2006). The disorder is characterised by hallucinations, delusions, cognitive disorganisation and mood problems, and is associated with an increased risk of maternal suicide or infanticide (Sit et al, 2006). The identification of biomarkers associated with increased risk is a key goal for ensuring early clinical intervention. Increased PP risk is associated with a personal or family history of psychotic disorder (notably bipolar disorder), with precipitous drops in circulating oestrogens following childbirth, with obstetric complications including pre-eclampsia, and with psychosocial stressors (Sit et al, 2006). Immune system (Bergink et al, 2013) and tryptophankynurenine pathway (Veen et al, 2016) disruptions have been demonstrated in PP, whilst regular smoking is associated with reduced risk (Di Florio et al, 2015)
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