Molecular Mechanisms of Reelin in the Enteric Nervous System and the Microbiota-Gut-Brain Axis: Implications for Depression and Antidepressant Therapy.

Current pharmacological treatments for depression fail to produce adequate remission in a significant proportion of patients. Increasingly, other systems, such as the microbiome-gut-brain axis, are being looked at as putative novel avenues for depression treatment. Dysbiosis and dysregulation along this axis are highly comorbid with the severity of depression symptoms. The endogenous extracellular matrix protein reelin is present in all intestinal layers as well as in myenteric and submucosal ganglia, and its receptors are also present in the gut. Reelin secretion from subepithelial myofibroblasts regulates cellular migration along the crypt-villus axis in the small intestine and colon. Reelin brain expression is downregulated in mood and psychotic disorders, and reelin injections have fast antidepressant-like effects in animal models of depression. This review seeks to discuss the roles of reelin in the gastrointestinal system and propose a putative role for reelin actions in the microbiota-gut-brain axis in the pathogenesis and treatment of depression, primarily reflecting on alterations in gut epithelial cell renewal and in the clustering of serotonin transporters.

A single intravenous reelin injection restores corticosterone-induced neurochemical and behavioral alterations in dams during the post-partum period.

Introduction: Treatment with the synaptic plasticity protein reelin has rapid antidepressant-like effects in adult corticosterone (CORT)-induced depressed rats, whether administered repeatedly or acutely. However, these effects remain unexplored in the context of post-partum depression (PPD). Methods: This study investigated the antidepressant-like effect of a single injection of reelin in a CORT-induced model of PPD. Long-Evans female dams received either daily subcutaneous CORT (40 mg/kg) or saline injections (controls) from the post-partum day (PD) 2 to 22, and on PD22 were treated with a single intravenous reelin (3 µg) or vehicle injection. Results: Reelin treatment fully normalized to control levels the CORT-induced increase in Forced Swim Test (FST) immobility and the decrease in reelin-positive cells in the subgranular zone of the intermediate hippocampus. It also increased the number of oxytocin-positive cells in the paraventricular nucleus (PVN), the number of reelin-positive cells in the dorsal and ventral hippocampus, and the dendritic complexity of newborn neurons in the intermediate hippocampus, causing a partial recovery compared to controls. None of these changes were associated with fluctuations in estrogen levels measured peripherally. Discussion: This study brings new insights into the putative antidepressant-like effect of peripherally administered reelin in an animal model of PPD. Future studies should be conducted to investigate these effects on a dose-response paradigm and to further elucidate the mechanisms underlying the antidepressant-like effects of reelin.

Time-dependent antidepressant-like effects of reelin and ketamine in the repeated-corticosterone model of chronic stress.

There is an urgent need for novel antidepressants, given that approximately 30% of those diagnosed with depression do not respond adequately to first-line treatment. Additionally, monoaminergic-based antidepressants have a substantial therapeutic time-lag, often taking months to reach full therapeutic effect. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist is the only current effective rapid-acting antidepressant, demonstrating efficacy within hours and lasting up to two weeks with an acute dose. Reelin, an extracellular matrix glycoprotein, has demonstrated rapid-acting antidepressant-like effects at 24 h, however the exact timescale of these effects has not been investigated. To determine the short and long-term effects of reelin, female Long Evans rats (n = 120) underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 days). On day 21, rats were treated with reelin (3µg; i.v.), ketamine (10 mg/kg; i.p.), both reelin and ketamine (same doses), or vehicle (saline). Behavioural and biological effects were then evaluated at 1 h, 6 h, 12 h, and 1 week after treatment. The 1-week cohort continued CORT injections to ensure the effect of chronic stress was not lost. Individually, both reelin and ketamine significantly rescued CORT-induced behaviour and hippocampal reelin expression at all timepoints. Ketamine rescued a decrease in dendritic maturity as induced by CORT. Synergistic effects of reelin and ketamine appeared at 1-week, suggesting a potential additive effect of the antidepressant-like actions. Taken together, this study provides further support for reelin-based therapeutics to develop rapid-acting antidepressant.