Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of major depressive disorder. A number of studies have shown that this dysregulation is correlated with impaired forebrain glucocorticoid receptor (GR) function. To determine whether a primary, acquired deficit in forebrain GR signaling is an etiologic factor in the pathogenesis of depression, we generated a line of mice with time-dependent, forebrain-specific disruption of GR (FBGRKO). These mice develop a number of both physiological and behavioral abnormalities that mimic major depressive disorder in humans, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis and, increased depression-like behavior. Importantly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant, imipramine. Our findings suggest that imipramine's proposed activities on forebrain GR function are not essential for its antidepressant effects, and that alteration in GR expression may play a causative role in disease onset of major depressive disorder. knockout mice M ajor depression is a serious neuropsychiatric illness that the World Health Organization predicts will soon be the world's greatest public health burden (www.nimh.nih.gov͞publicat͞ burden). Although both genetic and environmental factors are known to contribute to its pathogenesis, two fundamental questions remain unanswered. First, what are the primary genetic factors that contribute to a predisposition for depression? Second, what interacting biochemical pathways lead to the disease state? There are a number of lines of evidence that suggest that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may be a primary factor in the pathogenesis of depression (1). Depressed patients show hyperactivity of the HPA axis that may result from impairments in negative feedback regulation of glucocorticoid release (2). Moreover, normalization of these HPA axis abnormalities is associated with successful antidepressant treatment, and patients whose HPA abnormalities do not normalize are significantly more likely to relapse (3).Research both in humans and in animal models have implicated forebrain glucocorticoid receptors (GRs) in HPA axis regulation and depression (4, 5). Studies examining postmortem tissue from suicide victims and individuals with major depressive disorder (MDD) have revealed decreased GR mRNA expression in the hippocampus and cortex (6). Importantly, GR mRNA expression and hormone-binding activity are both increased after antidepressant treatment (7). In addition, a number of animal models of depression have been shown to be associated with decreased forebrain GR expression. In rodents, exposure to early life maternal neglect, which, in humans, is known to increase the risk of depression, leads to a depression like-phenotype (8) that is associated with decreased hippocampal GR expression (9). Conversely, an early nurturing environment led to increased hippocampal GR expression and decreased suscept...