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.

Adult neurogenesis in the mammalian dentate gyrus

“…Further evidence suggest that it is the dorsal hippocampus that is involved in spatial learning and memory, while the ventral hippocampus is more associated with limbic functions (Brooker, Gobeske, Chen, Peng, & Kessler, ; Hyer, Hunter, Katakam, Wolz, & Glasper, ; Kheirbek & Hen, ; Loxton & Canales, ; McHugh, Fillenz, Lowry, Rawlins, & Bannerman, ; Schoenfeld, McCausland, Sonti, & Cameron, ). Abnormalities in hippocampal function are associated with various neurological and psychiatric disorders in adults such as anxiety, schizophrenia and depression (Ampuero, Jury, Hartel, Marzolo, & Zundert, ; Brooker et al, ; Caruncho et al, ; Danzer, Kotloski, Walter, Hughes, & McNamara, ; Liu et al, ; Perez‐Domper et al, ; Yun et al, ).…”

“…Additional genes are newly expressed at this stage of maturation (Gonçalves et al, ), including brain‐derived neurotrophic factor (BDNF), Reelin, cAMP response element‐binding protein (CREB) and possibly activation protein transcription factor (AP‐1). Reelin, an extracellular glycoprotein, is highly expressed in hippocampal cells, both during development and in adult hippocampal GABAergic interneurons of many different species (Ampuero et al, ; Caruncho et al, ). Reelin influences many different aspects of hippocampal neurogenesis including neuronal fate and migration, the formation of dendritic spines and final integration of granule neurons into the hippocampal circuitry (Ampuero et al, ; Caruncho et al, ).…”

“…Reelin, an extracellular glycoprotein, is highly expressed in hippocampal cells, both during development and in adult hippocampal GABAergic interneurons of many different species (Ampuero et al, ; Caruncho et al, ). Reelin influences many different aspects of hippocampal neurogenesis including neuronal fate and migration, the formation of dendritic spines and final integration of granule neurons into the hippocampal circuitry (Ampuero et al, ; Caruncho et al, ). Cyclic adenosine 3,5‐monophosphate (cAMP) induces gene transcription by activating cAMP‐dependent protein kinase (PKA), which phosphorylates CREB and this pathway is important for promoting new neuron formation in the adult hippocampal dentate gyrus (Miyamoto et al, ; Zhang, Wang, & Lu, ; Zhang, Hong, Di, & Chen, ).…”

“…For example, the dorsal hippocampus appears to be involved in spatial learning and memory, while the ventral hippocampus is associated with stress, emotion and affect (Brooker et al, ; Hyer et al, ; Kheirbek & Hen, ; Loxton & Canales, ; McHugh et al, ; Schoenfeld et al, ). The hippocampus appears to have important functions in neurological and psychiatric disorders including anxiety, schizophrenia and depression (Ampuero et al, ; Brooker et al, ; Caruncho et al, ; Danzer et al, ; Liu et al, ; Perez‐Domper et al, ; Yun et al, ). Lesions in the ventral hippocampus and specifically ventral dentate gyrus lesions in rodents produce decreased anxiety‐like behaviour (Cameron & Glover, ).…”

Global epigenetic analysis of BDNF Val66Met mice hippocampus reveals changes in dendrite and spine remodeling genes

“…Reduced Reln mRNA and protein levels have been observed in postmortem brain regions of patients with schizophrenia and bipolar disorder, but not with major depression (Fatemi et al, ; Folsom & Fatemi, ; Guidotti et al, ). However, deficits in Reln expression have been also reported in animal models of depression (Caruncho et al, ). Interestingly, a recent study reported that blocking the Reln signaling pathway increases dendritic growth and branching in adult neurons, which is in contrast with previous studies showing that deficiency in Reln signaling impairs dendritic development (Ampuero et al, ).…”