MODELLING POLYGENICITY AND CLINICAL HETEROGENEITY OF MAJOR DEPRESSIVE DISORDERS TO IDENTIFY BIOMARKERS OF ANTIDEPRESSANT RESPONSE

Major depressive disorders (MDD) are predicted to become the leading cause of disease burden worldwide in 2030. However, 30% of patients still do not respond to antidepressants. Current rodent models of MDD mainly result 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 through selective breeding following 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 MDD model, called H-FST. Unlike our previous H-TST model, H-FST mice did not exhibit any anxiety- or anhedonia-like behaviours, nor did they display any sleep disturbances. Furthermore, H-TST and H-FST mice responded differently to antidepressant treatments. Gene expression level in the prefrontal cortex of H-TST and H-FST mice revealed little overlap between the genes and biological pathways associated with each model, as well as opposite dysregulation of excitatory/inhibitory synaptic balance. Finally, these two models allowed us to identify, biomarkers of treatment response specific of clinical subgroup of patients. Together, these mouse lines could model different subgroups of people with MDD and are valuable tools for developing precision medicine for mood disorders.