Reelin-Related Disturbances in Depression: Implications for Translational Studies

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.

Keywords: depression; hippocampus; lymphocytes; membrane protein clustering; neural plasticity; neurogenesis; reelin.

Figure 1

Graphical depiction of two possible mechanisms by which reelin down-regulation may be involved in the pathophysiology of depression. (A) Reelin secreted by some hippocampal GABAergic interneurons in the dentate subgranular zone (SGZ) as well as in cells in the distal molecular layer (shown in red) is involved in hippocampal neurogenesis, particularly the rate and extent of dendritogenesis of newborn granule cells (shown in blue). Repeated CORT administration reduces the number of reelin+ cells in the dentate SGZ and the amount of extracellular reelin in the distal molecular layer, which delays the maturation (e.g., reduced dendritogenesis) of newborn neurons. These neurons may fail to properly integrate into existing hippocampal circuits. (B) Reelin secreted by GABAergic interneurons promotes and stabilizes synapses impinging onto dendritic spines. The downregulation and neurochemical alterations of reelin-positive cells in the distal molecular layer and CA1 stratum-lacunosum-moleculare (shown in red) instigated by chronic stress would decrease in the number of dendritic spines, resulting in a loss of glutamatergic synaptic strength and possibly a dampening of neurotransmitter release from glutamatergic terminals (shown in blue). This would further affect hippocampal circuitry.

Figure 2

Schematic representation of alterations in membrane protein clustering in depression. One of the roles of peripheral reelin may be to regulate membrane protein clustering in lymphocytes (see text for details). If peripheral reelin is decreased in depression, the pattern of protein clustering in peripheral immune cells could be altered. The figure shows our findings that patients with depression have generally larger protein clusters (shown in green) along the lymphocyte plasma membrane than non-depressed subjects (see Rivera-Baltanás et al., 2012, 2014). We propose that alterations in protein clustering in depression patients could stimulate cytokine secretion, as has been frequently reported in depression.