Modelling the polygenicity and clinical heterogeneity of human depression in mice to identify biomarkers of antidepressant response

Major depressive disorders (MDD) are predicted to become the first cause of burden of disease worldwide in 2030, but 30% of patients still do not respond to antidepressants. Current rodent models of MDD mainly result either from one genetic or one environmental risk factor exposure, not recapitulating the multifactorial and polygenic nature of MDD. We recently generated a polygenic mouse model of MDD from selective breeding after mild stress in the Tail Suspension Test (TST), named H-TST. Here, we selected animals exhibiting high immobility during the Forced Swim Test (FST) to generate a new stable polygenic model of MDD, called H-FST. Unlike our previous H-TST model, H-FST mice did not exhibit any anxiety-or anhedonia-like behaviors, nor did they display any sleep disturbances. Moreover, H-TST and H-FST mice showed opposite response after administration of various antidepressant treatments. The gene expression level in the prefrontal cortex of H-TST and H-FST mice revealed little overlap in genes and biological pathways associated with depressive-like behaviors and opposite dysregulation of excitatory/inhibitory synaptic imbalance. Finally, these two models allowed in humans the identification biomarkers of treatment response specific of clinical subgroup of patients.