Abstract
Depression is a serious psychiatric disorder frequently comorbid with autoimmune disorders. Previous work in our lab has demonstrated that repeated corticosterone (CORT) injections in rats reliably increase depressive-like behavior, impair hippocampal-dependent memory, reduce the number and complexity of adult-generated neurons in the dentate gyrus, decrease hippocampal reelin expression, and alter markers of GABAergic function. We hypothesized that peripheral injections of the TNF-α inhibitor etanercept could exert antidepressant effects through a restoration of many of these neurobiological changes. To test this hypothesis, we examined the effect of repeated CORT injections and concurrent injections of etanercept on measures of object-location and object-in-place memory, forced-swim test behavior, hippocampal neurogenesis, and reelin and GABA β2/3 immunohistochemistry. CORT increased immobility behavior in the forced swim test and impaired both object-location and object-in-place memory, and these effects were reversed by etanercept. CORT also decreased both the number and complexity of adult-generated neurons, but etanercept restored these measures back to control levels. Finally, CORT decreased the number of reelin and GABA β2/3-ir cells within the subgranular zone of the dentate gyrus, and etanercept restored these to control levels. These novel results demonstrate that peripheral etanercept has antidepressant effects that are accompanied by a restoration of cognitive function, hippocampal neurogenesis, and GABAergic plasticity, and suggest that a normalization of reelin expression in the dentate gyrus could be a key component underlying these novel antidepressant effects.
Highlights
There is a strong connection between the immune system and the brain in the context of major depression
We found that the CORT + etanercept rats weighed significantly less than the vehicle and etanercept rats on day 14 (p-values < 0.05) and significantly less than the etanercept rats on day 21 (p = 0.021)
CORT induces internalization of GABAA receptors in the SGZ and this effect was partially rescued by etanercept. The results of this experiment show that prolonged exposure to the stress hormone CORT produces a cluster of effects characterized by increased immobility in the forced-swim test (FST), impaired spatial memory on the OBL and OBIP tests, reduced hippocampal neurogenesis, fewer SGZ reelin-ir cells, and dampened GABAA β2/3 expression levels
Summary
There is a strong connection between the immune system and the brain in the context of major depression. Chronic stress induces an inflammatory response, which in the central nervous system includes an increase in pro-inflammatory and a decrease in anti-inflammatory cytokines, in addition to the recruitment of microglia (Dantzer et al, 2008). Half of depressed patients display the hallmarks of a deregulated stress response, hypercortisolemia (Sachar and Baron, 1979). These high circulating levels of cortisol have pathological consequences for healthy brain functioning (Kendler and Gardner, 2010). Stress significantly increases depressive-like and anhedonia behavior (Sterner and Kalynchuk, 2010). Some of the most frequently reported elevated pro-inflammatory cytokines include IL-1, IL-6, and TNF-α (Dowlati et al, 2010), and general alterations in neuroimmune systems represent a key component underlying the neurobiology of both mood and psychotic disorders (Calcia et al, 2016; Wohleb et al, 2016; Rodrigues-Amorim et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
