Behavioural and neurobiological consequences of macrophage migration inhibitory factor gene deletion in mice.
BACKGROUND
Evidence from clinical studies and animal models show that inflammation can lead to the development of depression. Macrophage migration inhibitory factor (MIF) is an important multifunctional cytokine that is synthesized by several cell types in the brain. MIF can increase production of other cytokines, activates cyclooxygenase (COX)-2 and can counter-regulate anti-inflammatory effects of glucocorticoids. Increased plasma levels of MIF are associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and depressive symptoms in patients. In contrast, MIF knockout (KO) mice have been found to exhibit increased depressive-like behaviour. The exact role for MIF in depression is therefore still controversial. To further understand the role of MIF in depression, we studied depressive-like behaviour in congenic male and female MIF KO mice and wild-type (WT) littermates and the associated neurobiological mechanisms underlying the behavioural outcome.


METHODS
MIF KO and WT mice were tested for spontaneous locomotor activity in the open-field test, anhedonia-like behaviour in the sucrose preference test (SPT), as well as behavioural despair in the forced swim test (FST) and tail suspension test (TST). Brain and serum levels of cytokines, the enzymes COX-2 and indoleamine-2,3-dioxygenase (IDO) and the glucocorticoid hormone corticosterone were measured by RT-qPCR and/or high-sensitivity electrochemiluminescence-based multiplex immunoassays. Monoamines and metabolites were examined using HPLC.


RESULTS
We found that MIF KO mice of both sexes displayed decreased depressive-like behaviour as measured in the FST. In the TST, a similar, but non-significant, trend was also found. IFN-γ levels were decreased, and dopamine metabolism increased in MIF KO mice. Decreased brain IFN-γ levels predicted higher striatal dopamine levels, and high dopamine levels in turn were associated with reduced depressive-like behaviour. In the SPT, there was a sex-specific discrepancy, where male MIF KO mice showed reduced anhedonia-like behaviour whereas female KO mice displayed increased anhedonia-like behaviour. Our results suggest that this relates to the increased corticosterone levels detected in female, but not male, MIF KO mice.


CONCLUSIONS
Our findings support that MIF is involved in the generation of depressive-like symptoms, potentially by the effects of IFN-γ on dopamine metabolism. Our data further suggests a sex-specific regulation of the involved mechanisms.
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. cbr@clin.au.dk.
Cecilie
C
Bay-Richter
Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden. shorena.janelidze@med.lu.se.
Shorena
S
Janelidze
Department of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA. analise.sauro@hc.msu.edu.
Analise
A
Sauro
Department of Medicine, Yale School of Medicine, New Haven, CT, USA. richard.bucala@yale.edu.
Richard
R
Bucala
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA. jack.lipton@hc.msu.edu.
Jack
J
Lipton
Experimental Neuroinflammation Laboratory, Department of Experimental Medical Science, BMC, Lund University, Lund, Sweden. tomas.deierborg@med.lu.se.
Tomas
T
Deierborg
Department of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA. lena.brundin@hc.msu.edu.|Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, USA. lena.brundin@hc.msu.edu.
Lena
L
Brundin
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003863:Depression / Q000235:genetics*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005518:Food Preferences / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics*; D019417:Hindlimb Suspension / Q000523:psychology; D007249:Inflammation / Q000235:genetics*; D019746:Intramolecular Oxidoreductases / Q000172:deficiency* / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology
D015306:Biogenic Monoamines; D016207:Cytokines; D008263:Macrophage Migration-Inhibitory Factors; D013549:Sweetening Agents; D013395:Sucrose; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse; D003345:Corticosterone