Abstract
A growing body of evidence supports the close relationship between major depressive disorder (MDD), a severe psychiatric disease more common among women than men, and alterations of the immune/inflammatory system. However, despite the large number of studies aimed at understanding the molecular bases of this association, a lack of information exists on the potential cross-talk between systems known to be involved in depression and components of the inflammatory response, especially with respect to sex differences. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with a well-established role in MDD etiopathology: it is altered in depressed patients as well as in animal models of the disease and its changes are restored by antidepressant drugs. Interestingly, this neurotrophin is also involved in the inflammatory response. Indeed, it can be secreted by microglia, the primary innate immune cells in the central nervous system whose functions may be in turn regulated by BDNF. With these premises, in this study, we investigated the reciprocal impact of BDNF and the immune system by evaluating the neuroinflammatory response in male and female BDNF-heterozygous mutant mice acutely treated with the cytokine-inducer lipopolysaccharide (LPS). Specifically, we assessed the potential onset of an LPS-induced sickness behavior as well as changes of inflammatory mediators in the mouse hippocampus and frontal cortex, with respect to both genotype and sex. We found that the increased inflammatory response induced by LPS in the brain of male mice was independent of the genotype, whereas in the female, it was restricted to the heterozygous mice with no changes in the wild-type group, suggestive of a role for BDNF in the sex-dependent effect of the inflammatory challenge. Considering the involvement of both BDNF and neuroinflammation in several psychiatric diseases and the diverse incidence of such pathologies in males and females, a deeper investigation of the mechanisms underlying their interaction may have a critical translational relevance.
Highlights
Major depressive disorder (MDD) is a severe psychiatric disease affecting almost 10% of the general population and estimated to become the second leading cause of disability by 2020 (Bromet et al, 2011)
The mRNA levels of the pro-inflammatory cytokine TNF-α were measured in the hippocampus and in the frontal cortex of male (A,C) and female (B,D) wild-type (WT) and Brain-derived neurotrophic factor (BDNF) heterozygous (BDNF+/−) mice 24 h after a single injection of lipopolysaccharide (LPS, 400 μg/kg i.p). in comparison with mice treated with saline
The mRNA levels of CX3CL1 were measured in the hippocampus and in the frontal cortex of male (A,C) and female (B,D) wild-type (WT) and BDNF heterozygous (BDNF+/−) mice 24 h after a single injection of lipopolysaccharide (LPS, 400 μg/kg i.p). in comparison with mice treated with saline
Summary
Major depressive disorder (MDD) is a severe psychiatric disease affecting almost 10% of the general population and estimated to become the second leading cause of disability by 2020 (Bromet et al, 2011). In addition to the symptom heterogeneity among patients and to its complex etiology (Otte et al, 2016), MDD presents a sexually dimorphic nature, characterized by a twofold greater risk in females to develop the pathology (Brody et al, 2018; LeGates et al, 2019). On this basis and given the different immunological response in terms of innate and adaptive systems among sexes (Klein and Flanagan, 2016), it is plausible that sex-based differences in immune response might play an important role to the diverse vulnerability/incidence to psychiatric disorders (Derry et al, 2015; Rubinow and Schmidt, 2019). While changes in immune/inflammatory response have been found in MDD experimental models based on both the genetic and the environmental components of the disease (Chourbaji et al, 2011; Couch et al, 2013; Macchi et al, 2013; Rossetti et al, 2016; Wang et al, 2018), several studies indicate the immune/inflammatory system as a potential target for the pharmacological treatment of MDD (Molteni et al, 2013; Kv et al, 2018; Rossetti et al, 2018a,b; Lu et al, 2019)
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 call
