Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors.
Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.
Conboy
L
L
Laboratory of Behavioral Genetics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.
Varea
E
E
Castro
J E
JE
Sakouhi-Ouertatani
H
H
Calandra
T
T
Lashuel
H A
HA
Sandi
C
C
D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002097:C-Reactive Protein / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D003345:Corticosterone / Q000097:blood / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005239:Fear; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000378:metabolism*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011987:Receptors, Steroid / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects; D000099153:Pentraxins
D018687:Antidepressive Agents, Second-Generation; D001973:Bromodeoxyuridine; D002097:C-Reactive Protein; D003345:Corticosterone; D005473:Fluoxetine; D008263:Macrophage Migration-Inhibitory Factors; D009419:Nerve Tissue Proteins; D011987:Receptors, Steroid; D000099153:Pentraxins