Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF.
Ceruloplasmin (Cp) is a ferroxidase involved in iron metabolism by converting Fe(2+) to Fe(3+), and by regulating cellular iron efflux. In the ceruloplasmin knockout (CpKO) mouse, the deregulation of iron metabolism results in moderate liver and spleen hemosiderosis, but the impact of Cp deficiency on brain neurochemistry and behavior in this animal model is unknown. We found that in contrast to peripheral tissues, iron levels in the hippocampus are significantly reduced in CpKO mice. Although it does not cause any discernable deficits in motor function or learning and memory, Cp deficiency results in heightened anxiety-like behavior in the open field and elevated plus maze tests. This anxiety phenotype is associated with elevated levels of plasma corticosterone. Previous studies provided evidence that anxiety disorders and long-standing stress are associated with reductions in levels of serotonin (5HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus. We found that levels of 5HT and norepinephrine (NE), and the expression of BDNF and its receptor trkB, are significantly reduced in the hippocampus of CpKO mice. Thus, Cp deficiency causes an anxiety phenotype by a mechanism that involves decreased levels of iron, 5HT, NE, and BDNF in the hippocampus.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sarah J
SJ
Texel
Simonetta
S
Camandola
Bruce
B
Ladenheim
Sarah M
SM
Rothman
Mohamed R
MR
Mughal
Erica L
EL
Unger
Jean Lud
JL
Cadet
Mark P
MP
Mattson
D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000523:psychology*; D001923:Brain Chemistry / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency*; D002570:Ceruloplasmin / Q000172:deficiency* / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D005239:Fear / Q000502:physiology; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000378:metabolism*; D000090463:Iron Deficiencies; D007858:Learning / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D004856:Postural Balance / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D021641:Recognition, Psychology / Q000502:physiology; D012701:Serotonin / Q000172:deficiency*; D014158:Transcription, Genetic
D019208:Brain-Derived Neurotrophic Factor; D012701:Serotonin; D002570:Ceruloplasmin; D003345:Corticosterone