ReviewRole of vascular endothelial growth factor in adult hippocampal neurogenesis: Implications for the pathophysiology and treatment of depression
Highlights
► Stress decreases and antidepressant treatment increases VEGF levels in limbic structures of the brain, most notably hippocampus. ► VEGF is necessary and sufficient for the neurogenic and behavioral actions of antidepressant treatments. ► Rapid and robust induction of VEGF expression can increase the proliferation of quiescent neural progenitor cells, and lead to a robust increase in neurogenesis.
Introduction
Major depressive disorder (MDD) is a highly debilitating and pervasive illness affecting as many as one in five Americans [1]. Given that MDD is a leading cause of disability worldwide [2], a high priority of current research is to understand the cellular and molecular mechanisms underlying depression, including both its pathogenesis and recovery. Despite the difficulty in elucidating the neural substrates of MDD [3], a growing body of evidence has suggested that dysfunction of the hippocampus may underlie, at least in part, the etiology and treatment of this disorder [4], [5]. Recent neuroimaging and histopathological studies of postmortem tissue have confirmed this view and provide some interesting clues about the nature of the cellular changes in the hippocampus of depressed patients [6]. Along these lines, one of the most consistent findings reported in the literature is decreased hippocampal volume and altered cell morphology in patients with MDD, especially those with a long history of pharmacoresistant depression [7], [8], [9], [10], [11]. In addition, preclinical studies have also demonstrated that exposure to high levels of glucocorticoids or chronic stress can result in neuronal atrophy and cell loss in this region [12], [13]. Although several different mechanisms could contribute to the structural alterations and neuronal loss in the hippocampus, one of the most intriguing findings to emerge from this research is the possible involvement of neurogenesis in the etiology and treatment of stress-related illnesses, notably MDD.
Previously, it was believed that neurogenesis was restricted mainly to prenatal or early postnatal periods. However, over the last two decades, it has been shown that new neurons are continuously generated in discrete regions of the brain throughout life leading to wide acceptance that neurogenesis occurs in the adult brain. The two major germinal sites, the anterior portion of the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus, serve as the main regions of neurogenesis in the mature brain. Adult hippocampal neurogenesis in particular has received extensive study mainly due to its phylogenetic conservation across multiple species, including non-human primates and humans [14], [15], [16], and its possible relevance in various neuropsychiatric and neurological conditions, as well as playing a role in cognitive processes such as learning and memory. In the context of MDD, preclinical studies have found that stress and chronic antidepressant treatment exert opposing effects on hippocampal neurogenesis. That is, stress generally results in a reduction in hippocampal neurogenesis and chronic antidepressant treatments increase neurogenesis [17], [18] suggesting that adult hippocampal neurogenesis may be an important component in the therapeutic action of antidepressants.
Significant progress has been made at uncovering the molecular signals that regulate the division of neuronal progenitors in the adult hippocampus and could serve as potential candidates in the treatment of MDD. In this review, we will discuss one such target, vascular endothelial growth factor (VEGF), and the role of this multifunctional growth factor in both the pathophysiology and treatment of depression. We will first provide an overview of the neurogenic/neurotrophic hypothesis of depression and the role of VEGF signaling in adult neurogenesis. Finally, we will present the current state of knowledge of VEGF in animal models of stress and in the behavioral action of antidepressants.
Section snippets
The neurogenic/neurotrophic hypothesis of depression
The birth of new cells in the adult hippocampus of rodents can be detected by the presence of cells labeled by an injection with the DNA synthesis marker bromodeoxyuridine (BrdU) or by examining the expression of endogenous cell cycle marker proteins (e.g., PCNA, Ki67, phosphohistone H3). In the adult rat hippocampus, it has been estimated that over 9000 new cells are born each day [19]. Of the dividing cells that survive (∼50%) [20], the vast majority express markers of neuronal lineage (e.g.,
Neurotrophic factors regulating neurogenesis
The mechanism(s) through which antidepressants increase hippocampal neurogenesis has been the subject of intense experimental investigation. Although early theories of antidepressant action focused mainly on the ability of these compounds to reverse imbalances in monoamine neurotransmitters, such as dopamine, noradrenalin, and serotonin, it has become increasingly clear that elevations in intrasynaptic levels of biogenic amines alone cannot account for the therapeutic efficacy of
VEGF and depression: blood, sweat, and tears
Recently, there has been intense effort made to examine the role of vascular dysfunction in the development of MDD. It has been known that cerebrovascular diseases, including stroke, are associated with a high incidence of MDD [111]. Decreased cerebral blood flow and metabolism in the hippocampus and prefrontal cortices are frequently found in patients with treatment resistant depression [112], [113]. In this context, it is worth mentioning that endothelial cell dysfunction, decreased
Future directions and conclusions
The prevalence of MDD is on the rise, resulting in an enormous health care burden that not only affects the individual but permeates throughout all avenues of social, work, and family life. Progress has been made in revealing candidate molecular pathways and neural substrates that could serve as important targets for pharmacological intervention. Strategies targeting adult hippocampal neurogenesis have received considerable attention in the possible treatment of MDD. However, several key
Acknowledgements
This work is supported by USPHS grants MH45481 (RSD), 2 P01 MH25642 (RSD), the Connecticut Mental Health Center (RSD), and a postdoctoral fellowship award from the Natural Sciences and Engineering Council of Canada (NMF).
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