Role of Interferon-Gamma and Leucine-Rich Repeat Kinase 2 in Stress-Related Pathology

Pro-inflammatory cytokines promote stressor-like behavioural and neurochemical variations and are implicated in depression. Despite being a preferential inducer of the depression-linked inflammatory enzyme indoleamine 2,3-dioxygenase, the T-helper type-1 cytokine interferon gamma (IFN-γ) has received little attention in preclinical animal models. In the current studies we set out to elucidate the role of IFN-γ in stressor-related psychological pathology. In Chapter 2 we show that IFN-γ deficiency in mice attenuated some of the corticosterone, cytokine and brain regional dopaminergic effects of chronic stress. Similarly, in Chapter 3 we report that a lack of IFN-γ not only protected against stressor-induced memory dysfunction but also appeared to facilitate memory performance following stress. Surprisingly, however, under basal conditions the IFN-γ knockout mice actually had increased plasma corticosterone levels, heightened brain regional noradrenergic and serotonergic activity, and impaired spatial memory function, suggesting that a certain basal level of IFN-γ is required for the homeostatic regulation of these behavioural and physiological systems. Building on the findings from these two IFN-γ knockout studies we next undertook to ascertain whether the cytokine proactively affects depression-relevant pathophysiological domains. In Chapters 4 and 5 we demonstrate that systemically administered IFN-γ (25000 IU) mobilized peripheral cytokine networks, stimulated brain regional monoaminergic activity and sensitized the plasma corticosterone response to psychological stress. However, the cytokine did not alter locomotor activity or cause sickness-type behaviours in either of these studies. Additionally, in Chapter 5 we show that the monoaminergic effects of IFN-γ and bacterial lipopolysaccharide were exaggerated in mice overexpressing a mutated form of the Parkinson’s disease-linked factor leucine-rich repeat kinase 2 (i.e., LRRK2 G2019S). In this way, we provide preliminary proof-of-concept for an IFN-γ-LRRK2 signalling pathway that may be relevant for depression and other non-motor symptoms in PD. Overall the findings presented in this thesis support a role for IFN-γ in stressor-related pathology and provisionally implicate LRRK2 as a novel downstream mediator of the cytokine’s depressogenic effect. Further studies are warranted to verify and extend the pathological significance of these findings.