Reelin, the HPA Axis, and Chronic Stress: Implications for the Neurobiology of Depression

Stress and associated dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to major depression etiology, as HPA axis hyperactivity and hypercortisolism are common occurrences in individuals with depression. Reelin, an extracellular matrix glycoprotein that plays numerous roles in brain development and function, is downregulated in several neuropsychiatric disorders. Reelin and its receptors are present throughout the HPA axis, and research has found that reelin levels are decreased in animal models of chronic stress in the hypothalamus. There may therefore be roles for reelin in regulating aspects of healthy HPA axis function and for reelin supplementation in restoring various facets of HPA axis function in chronic stress conditions, particularly those associated with HPA axis inhibition and stimulation. This review aims to summarize proposed roles for reelin in HPA axis activity, with a focus on the direct and indirect roles of reelin in restoring HPA axis homeostasis in chronic stress and depression. This review will explore possible interactions between reelin and the HPA axis in chronic stress conditions in order to expand our understanding of the mechanisms underlying the neurobiology of depression.