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 iii 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. List of Abbreviations3-HK, 3-hydroxykynurenine 5-HIAA, 5-hydroxyindole acetic acid 5-HT, serotonin 6-OHDA, 6-hydroxydopamine ACTH, adrenocorticotropic hormone AD, Alzheimer's disease AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ANK, ankyrin repeat motif ANOVA, analysis of variance ARM, armadillo repeat motif BAC, bacterial artificial chromosome BBB, blood-brain barrier BDNF, brain-derived neurotrophic factor BH4, 5,6,7,8-tetrahydrobiopterin CeA, central amygdala CNS, central nervous system COR, C-terminal of ROC COX-2, cyclooxygenase-2 CREB, cyclic adenosine 3',5'-monophosphate response element binding protein CRH, corticotropin-releasing hormone CRP, C-reactive protein CSF, cerebrospinal fluid CVO, circumventricular organ DA, dopamine DAT, dopamine transporter DI, discrimination index DNA, deoxyribonucleic acid DOPAC, 3,4-dihydroxyphenylacetic acid EDTA disodium salt, disodium ethylenediaminetetraacetate dehydrate ELISA, enzyme-linked immunosorbent assay ERK-1/2, extracellular signal-regulated kinase (mitogen-activated protein kinase)-1/2 FST, forced swim test G2019S, glycine-to-serine substitution at position 2019 GABA, gamma-aminobutyric acid GAS, gamma activation sequence GDNF, glial-derived neurotrophic factor GR, glucocorticoid receptor GS-Tg, LRRK2 G2019S transgenic GTP, guanosine-5'-triphosphate HC, hippocampus HIV/AIDS, human immunodeficiency virus infection and acquired immune deficiency syndrome HPA, hypothalamic-pituitary-adrenal HPLC, high-performance liquid chromatography Hsp90, heat shock protein 90 xiii HVA, homovanillic acid IDO, indoleamine 2,3-dioxygenase IFN, interferon IGF, insulin-like growth factor IL, interleukin iNOS, inducible nitric oxide synthase IRF, interferon regulatory factor ISRE, interferon-stimulated response element Jak, janus family tyrosine kinase JNK, c-Jun N terminal kinase KO, knockout KYN, kynurenine KYNA, kynurenic acid LC, locus coeruleus LPS, lipopolysaccharide LRRK2, leucine-rich repeat kinase 2 LTP, long-term potentiation MAO, monoamine oxidase MAPK, mitogen-activated protein kinase MCP-1/CCL2, monocyte chemoattractant protein-1 MHC, major histocompatibility complex MHPG, 3-methoxy-4-hydroexyphenylglycol mRNA, messenger ribonucleic acid Myd88, myeloid differentiation primary response protein NAcc, nucleus accumbens NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase NE, norepinephrine NET, norepinephrine transporter NF-κB, nuclear factor-kappa B NK, natural killer NMDA, N-methyl-D-aspartate NO, nitric oxide NSF, N-ethylmaleimide-sensitive factor p38 MAPK, p38 mitogen-activated protein kinase PD, Parkinson's disease PFC, prefrontal cortex PKB, protein kinase B/Akt Poly I:C, polyinosinic-polycytidylic acid QUIN, quinolinic acid R1441G, arginine-to-glycine substitution at position 1441 ROS, reactive oxygen species SERT, serotonin transporter SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor SNc, substantia nigra pars compacta SSRI, selective serotonin reuptake inhibitor Stat, signal transducer and activator of transcription xiv Tat, HIV-1 trans-activator of transcription Tg, transgenic Th1/2, T-helper type-1/2 TLR, Toll-like receptor TNF, tumor necrosis factor TRP, tryptophan VMAT2, vesicular monoamine transporter 2 WT, wild-type xv Preface This thesis is primarily based on the following 4 manuscripts, each of which comprises a separate research chapter in the present document.The use of copyrighted material, namely Litteljohn et al. (2010b) and Litteljohn et al. (2014), is hereby acknowledged.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.