Mood disorders are the most common psychiatric disorders. Although the mechanisms implicated in the genesis of mood disorders are still unclear, stress is known to predispose to depression, and recently, studies have related hippocampal neurogenesis and apoptosis to depression. In the present study we first examined the balance between cell birth-death in the hippocampus and subventricular zone (SVZ) of pre-pubertal and adult rats subjected to chronic-mild-stress (CMS). CMS led to increased corticosterone secretion and induced depressive-like symptoms (assessed in the forced-swimming test); these endocrine and behavioral effects were paralleled by decreased hippocampal, but not SVZ, cell proliferation/differentiation and by increased apoptotic rate. In order to determine if lithium, a known mood stabilizer with antidepressant properties, could prevent the stress-induced events, we analyzed the same parameters in a group of rats treated with lithium during the stress exposure period (CMS+Li) and observed that the hormonal, behavioral and cell turnover effects of CMS were abrogated in these animals. Subsequently, to search for possible pathways through which CMS and lithium influence behavior, cell fate and synaptic plasticity, we analyzed the expression of glycogen-synthase-kinase-3beta (GSK-3beta), as well as some of its downstream targets (B-cell-CLL/lymphoma2-associated athanonege (BAG-1) and synapsin-I). CMS increased GSK-3beta and decreased synapsin-I and BAG-1 expression in the hippocampus. Interestingly, co-administration of lithium precluded the CMS-induced effects in GSK-3beta, synapsin-I and BAG-1 expression. Our observation that specific inhibition of this kinase with AR-A014418 blocked the effects of CMS in depressive-like behavior and in BAG-1 and synapsin-I expression confirmed the involvement of the GSK-3beta pathway in stress-induced effects. In summary, these results reveal that lithium, by regulating the activity of GSK-3beta, prevents the deleterious effects of stress on behavior and cellular functions.