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Front. Pharmacol. | doi: 10.3389/fphar.2018.00121

Peripheral etanercept administration normalizes behavior, hippocampal neurogenesis, and hippocampal reelin and GABAA receptor expression in a preclinical model of depression

  • 1University of Saskatchewan, Canada
  • 2University of Victoria, Canada

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 GABAB2/3 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 GABAB2/3-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.

Keywords: etanercept, Neurogenesis, reelin, Hippocampus, Depression, antidepressant

Received: 15 Dec 2017; Accepted: 02 Feb 2018.

Edited by:

Ashok Kumar, University of Florida, United States

Reviewed by:

Yogesh Dwivedi, University of Alabama at Birmingham, United States
Luigia Trabace, University of Foggia, Italy  

Copyright: © 2018 Brymer, Fenton, Kalynchuk and Caruncho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Hector J Caruncho, University of Victoria, Victoria, Canada, hectorjcaruncho@uvic.ca