Systemic treatment with GnRH agonist produces antidepressant-like effects in LPS induced depression male mouse model

Abstract

Abstract Background Neuroinflammation is considered as a key mediator of depression. Therefore, understanding the pathophysiological mechanisms by which neuroinflammation and depression are linked can benefit novel therapies. Gonadotropin-releasing hormone (GnRH) is at the head of the neuroendocrine reproductive axis. However, the non-reproductive functions of GnRH expressed in various tissues, including hippocampus, are still not known. Methods We combined viral tool, neuropharmacology, and behavioral tests in male mice to test whether GnRH affects neuroinflammation that mediates LPS induced depression-like behavior. Results Both systemic treatment with GnRH agonist and over-expression of endogenous hippocampal GnRH via viral tool abolished the depression-like behavior after LPS challenges in mice. Conversely, antagonizing GnRHR by drug treatment or by hippocampal GnRHR knockdown could block the antidepressant- effect of GnRH agonist. Interestingly, we found that the peripheral GnRH treatment prevented the microglia activation mediated inflammation in the hippocampus of mice. Conclusion We propose that, at least in the hippocampus, GnRH appears to act on GnRHR to regulate higher order non-reproductive functions associated with the microglia mediated neuroinflammation. These findings also provide insights into the function and cross-talk of GnRH, a known neuropeptide hormone, in neuro-immune response.