Early-life stress and antidepressant treatment involve synaptic signaling and Erk kinases in a gene-environment model of depression.

Stress has been shown to interact with genetic vulnerability in pathogenesis of psychiatric disorders. Here we investigated the outcome of interaction between genetic vulnerability and early-life stress, by employing a rodent model that combines an inherited trait of vulnerability in Flinders Sensitive Line (FSL) rats, with early-life stress (maternal separation). Basal differences in synaptic signaling between FSL rats and their controls were studied, as well as the consequences of early-life stress in adulthood, and their response to chronic antidepressant treatment (escitalopram). FSL rats showed basal differences in the activation of synapsin I and Erk1/2, as well as in alpha CaM kinase II/syntaxin-1 and alpha CaM kinase II/NMDA-receptor interactions in purified hippocampal synaptosomes. In addition, FSL rats displayed a blunted response of Erk-MAP kinases and other differences in the outcome of early-life stress in adulthood. Escitalopram treatment restored some but not all alterations observed in FSL rats after early-life stress. The marked alterations found in key regulators of presynaptic release/neurotransmission in the basal FSL rats, and as a result of early-life stress, suggest synaptic dysfunction. These results show that early gene-environment interaction may cause life-long synaptic changes affecting the course of depressive-like behavior and response to drugs.