Abstract
The finding that reelin expression is significantly decreased in mood and psychotic disorders, together with evidence that reelin can regulate key aspects of hippocampal plasticity in the adult brain, brought our research group and others to study the possible role of reelin in the pathogenesis of depression. This review describes recent progress on this topic using an animal model of depression that makes use of repeated corticosterone (CORT) injections. This methodology produces depression-like symptoms in both rats and mice that are reversed by antidepressant treatment. We have reported that CORT causes a decrease in the number of reelin-immunopositive cells in the dentate gyrus subgranular zone (SGZ), where adult hippocampal neurogenesis takes place; that down-regulation of the number of reelin-positive cells closely parallels the development of a depression-like phenotype during repeated CORT treatment; that reelin downregulation alters the co-expression of reelin with neuronal nitric oxide synthase (nNOS); that deficits in reelin might also create imbalances in glutamatergic and GABAergic circuits within the hippocampus and other limbic structures; and that co-treatment with antidepressant drugs prevents both reelin deficits and the development of a depression-like phenotype. We also observed alterations in the pattern of membrane protein clustering in peripheral lymphocytes in animals with low levels of reelin. Importantly, we found parallel changes in membrane protein clustering in depression patients, which differentiated two subpopulations of naïve depression patients that showed a different therapeutic response to antidepressant treatment. Here, we review these findings and develop the hypothesis that restoring reelin-related function could represent a novel approach for antidepressant therapies.
Highlights
BRIEF HISTORY OF REELIN IN THE NERVOUS SYSTEMThe reeler mouse has been widely studied since the 1950’s as a model to understand neural development and developmental dysregulations (reviewed in Lambert de Rouvroit and Goffinet, 1998)
We have reported that CORT causes a decrease in the number of reelin-immunopositive cells in the dentate gyrus subgranular zone (SGZ), where adult hippocampal neurogenesis takes place; that down-regulation of the number of reelin-positive cells closely parallels the development of a depression-like phenotype during repeated CORT treatment; that reelin downregulation alters the co-expression of reelin with neuronal nitric oxide synthase; that deficits in reelin might create imbalances in glutamatergic and GABAergic circuits within the hippocampus and other limbic structures; and that co-treatment with antidepressant drugs prevents both reelin deficits and the development of a depression-like phenotype
Taking into account the just mentioned alterations in immune cells in mice expressing low levels of reelin, as well as the disturbances in reelin immunoreactive cells in the dentate gyrus of both depressive patients (Fatemi et al, 2000) and rats showing depression-like behavior (Lussier et al, 2013a), we examined the pattern of lymphocyte membrane protein clustering in peripheral blood samples taken from rats treated with repeated CORT injections and from patients with depression both before treatment and after 8 weeks of antidepressant drug treatment
Summary
The reeler mouse has been widely studied since the 1950’s as a model to understand neural development and developmental dysregulations (reviewed in Lambert de Rouvroit and Goffinet, 1998). This suggested to us that stress-induced alterations in reelin-expressing GABAergic interneurons located adjacent to the SGZ could influence the course of hippocampal neurogenesis To investigate this idea, we compared the time course of changes in the number of reelin-positive cells in the SGZ, the maturation rate of newborn granule neurons, and the onset of a depressionlike phenotype in rats subjected to 7, 14, or 21 days of CORT injections. We found that CORT-treated rats showed gradual increases in depression-like behavior over the course of the injections, which were paralleled by significant decreases in SGZ reelin expression (no changes at 7 days, 25% decrease at 14 days, and 26% decrease at 21 days) and significant decreases in the number of surviving immature dentate granule cells and the complexity of dendritic processes present in surviving immature granule cells (Lussier et al, 2013a) We interpreted these observations to indicate that reelin downregulation may delay the maturation of newborn granule cells and impair proper integration of these neurons into mature circuits, thereby disrupting hippocampal circuitry and enhancing depression-like behavior. The identification of this mechanism is an important step, which could inform the development of novel antidepressant drugs or mechanisms of action for antidepressant drug actions (see discussion below)
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