A novel murine model to study the impact of maternal depression and antidepressant treatment on biobehavioral functions in the offspring

Joseph Scarborough,Flavia S Mueller,Annamaria Cattaneo,Juliet Richetto,Lennart Opitz,Ulrike Weber-Stadlbauer,Daniele Mattei

doi:10.1038/s41380-021-01145-7

Abstract

Antenatal psychopathology negatively affects obstetric outcomes and exerts long-term consequences on the offspring’s wellbeing and mental health. However, the precise mechanisms underlying these associations remain largely unknown. Here, we present a novel model system in mice that allows for experimental investigations into the effects of antenatal depression-like psychopathology and for evaluating the influence of maternal pharmacological treatments on long-term outcomes in the offspring. This model system in based on rearing nulliparous female mice in social isolation prior to mating, leading to a depressive-like state that is initiated before and continued throughout pregnancy. Using this model, we show that the maternal depressive-like state induced by social isolation can be partially rescued by chronic treatment with the selective serotonin reuptake inhibitor, fluoxetine (FLX). Moreover, we identify numerous and partly sex-dependent behavioral and molecular abnormalities, including increased anxiety-like behavior, cognitive impairments and alterations of the amygdalar transcriptome, in offspring born to socially isolated mothers relative to offspring born to mothers that were maintained in social groups prior to conception. We also found that maternal FLX treatment was effective in preventing some of the behavioral and molecular abnormalities emerging in offspring born to socially isolated mothers. Taken together, our findings suggest that the presence of a depressive-like state during preconception and pregnancy has sex-dependent consequences on brain and behavioral functions in the offspring. At the same time, our study highlights that FLX treatment in dams with a depression-like state can prevent abnormal behavioral development in the offspring.

Highlights

Pregnancy is a delicate period that relies on a balance between personal, family-related and employment-related issues
social isolation rearing (SIR) females displayed increased anxiety-like behavior in the light-dark box test, as evident by the increased latency to shuttle from the dark to the bright compartment of the testing apparatus (t(78) = 3.683, p < 0.001, Fig. 1d)
Half of the SIR and GRP mice were subjected to chronic FLX treatment at 7 weeks after isolation rearing or group housing, whereas the other half of mice was assigned to vehicle (VEH) treatment (Fig. 1a)

Summary

Introduction

Pregnancy is a delicate period that relies on a balance between personal, family-related and employment-related issues. In instances where this balance is not attainable, pregnancy can become a stress-inducing situation, which in turn compromises the mother and offspring’s wellbeing [1]. The use of antidepressant drugs (ADDs) during pregnancy has greatly increased, and is expected to escalate given the overall rise of depression worldwide [6, 7]. The most commonly prescribed ADDs are selective serotonin reuptake inhibitors (SSRIs), which have been considered moderately safe for antenatal use [6, 8, 9]. SSRIs act by inhibiting the serotonin transporter, blocking the reabsorption of serotonin by presynaptic neurons and increasing its availability in the synaptic cleft [10]

Methods

Results

Conclusion