Towards new insights in psychiatric disorders: expression profiles of inflammation-related genes in murine models of sickness behaviour

Recent studies suggest that major depressive disorder (MDD), whose etiology is still unknown, might be determined by inflammatory processes and interactions among the neuroendocrine and the immune system. Interleukin-1β (IL-1β) is a key component of inflammatory processes and it has recently been shown to be involved in MDD. It has been suggested to act in the central nervous system (CNS) both by inducing the symptoms observed in sickness behaviour – that mimic the psychological condition of depressive symptoms – and by decreasing neurogenesis in the hippocampus. We hypothesized that pro-inflammatory genes, interplaying with IL-1β, are directly involved in the pathophysiology of MDD. To test this hypothesis, we used wild-type (WT) mice and mice genetically deprived of major components of the innate immune response inflammatory arm, such as NOS2-/- and casp1-/- mice. NOS2 knockout mice lacked a potent pro-inflammatory mediator, the inducible form of nitric oxide synthase (NOS2), whereas casp1 knockout mice lacked the mature and biologically active form of IL-1β. All these mice have been treated with lypopolysaccharide (LPS), which is a potent bacterial endotoxin that induces sickness behavior in murine models. Using quantitative Real-Time PCR we have characterized for all these mice groups the spatial-temporal expression of nine inflammatory-related genes – a disintegrin and metalloproteinase with thrombospondin repeats (ADAMTs1), cyclooxigenase 2 (COX2), nitric oxide synthase 2 (NOS2), chemoattractant cytokines 1 and 10 (CXCL1 and CXCL10), lipocalin 2 (LCN2), T-cell specific GTPase (TGTP), guanylate binding protein 2 (GBP2), and IL-1 receptor antagonist (IL1RA) – and of two genes associated with other psychiatric disorders – latrophilin 3 (LPHN3, previously associated with attention deficit/hyperactivity disorder) and disrupted in schizophrenia 1 (DISC1, previously associated with schizophrenia). The profiles of expression of these 11 genes have been investigated within the hippocampus, a region of the CNS associated with mood control and memory formation, and in two peripheral organs representing the immune (spleen) and the endocrine system (adrenal glands). After challenging the murine models with LPS, we observed exacerbated sickness behavior that led to 100% lethality in WT and NOS2-/- mice between 12-24 hs. On the other hand, although casp1-/- models displayed an inflammatory response, 100% of these mice survived the LPS-induced lethality after 24h. Notably, we detected a high inflammatory response in the hippocampus of all mice, indicating that the effects of LPS-induced IL-1β are indeed strongly activated in the brain, as well as in peripheral organs. Moreover, we observed a nearly 30% decrease in late hippocampal activation of COX2, NOS2, IL-1RA, and LCN2 genes in casp1-/- mice, and differences in patterns of expression of the genes in study among different tissues, as well. Taken together, our results suggest that casp1-/- mice are more protected against neuro-inflammation induced by LPS than other mice, and this strengthens the hypothesis that IL-1β might play the most important stimulant role in the regulation of inflammation-related genes. Also, differential patterns of expression among tissues suggested that neuro-inflammatory processes might be temporally consequent to LPS-induced peripheral inflammation. Through our results, we were able to hypothesize a pathophysiological mechanism depicting the role played by each of the genes in study in the complex inflammatory, endocrine and neural networks finally converging into a state of sickness behaviour or depression. These processes hypothetically involve the activation of inflammation pathways in cerebral areas, with a consequent impairment of neurogenesis and changes in brain areas involved in mood regulation.