Kynurenine pathway metabolites are associated with hippocampal activity during autobiographical memory recall in patients with depression.
Inflammation-related changes in the concentrations of inflammatory mediators such as c-reactive protein (CRP), interleukin 1β (IL-1), and IL-6 as well as kynurenine metabolites are associated with major depressive disorder (MDD) and affect depressive behavior, cognition, and hippocampal plasticity in animal models. We previously reported that the ratios of kynurenic acid (KynA) to the neurotoxic metabolites, 3-hydroxykynurenine (3HK) and quinolinic acid (QA), were positively correlated with hippocampal volume in depression. The hippocampus is critical for autobiographical memory (AM) recall which is impaired in MDD. Here we tested whether the ratios, KynA/3HK and KynA/QA were associated with AM recall performance as well as hippocampal activity during AM recall. Thirty-five unmedicated depressed participants and 25 healthy controls (HCs) underwent fMRI scanning while recalling emotionally-valenced AMs and provided serum samples for the quantification of kynurenine metabolites, CRP, and cytokines (IL-1 receptor antagonist - IL-1RA; IL-6, tumor necrosis factor alpha - TNF, interferon gamma -IFN-γ, IL-10). KynA/3HK and KynA/QA were lower in the MDD group relative to the HCs. The concentrations of the CRP and the cytokines did not differ significantly between the HCs and the MDD group. Depressed individuals recalled fewer specific AMs and displayed increased left hippocampal activity during the recall of positive and negative memories. KynA/3HK was inversely associated with left hippocampal activity during specific AM recall in the MDD group. Further, KynA/QA was positively correlated with percent negative specific memories recalled in the MDD group and showed a non-significant trend toward a positive correlation with percent positive specific memories recalled in HCs. In contrast, neither CRP nor the cytokines were significantly associated with AM recall or activity of the hippocampus during AM recall. Conceivably, an imbalance in levels of KynA versus QA-pathway metabolites may adversely impact the function of the hippocampus and AM recall, raising the possibility that kynurenine pathway may affect emotion-dependent memory within the context of depression.
Laureate Institute for Brain Research, Tulsa, OK, USA.
Kymberly D
KD
Young
Janssen Research & Development, LLC, of Johnson & Johnson Inc., Titusville, NJ, USA.
Wayne C
WC
Drevets
Division of Internal Medicine, Department of Symptom Research, MD Anderson Cancer Center, Houston, TX, USA.
Robert
R
Dantzer
Departments of Surgery and Psychiatry, University of Oklahoma College of Medicine, Tulsa, OK, USA; Department of Pharmaceutical Sciences, University of Oklahoma College of Pharmacy, Tulsa, OK, USA; Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA.
T Kent
TK
Teague
Laureate Institute for Brain Research, Tulsa, OK, USA; College of Engineering, University of Oklahoma, Tulsa, OK, USA.
Jerzy
J
Bodurka
Laureate Institute for Brain Research, Tulsa, OK, USA; Faculty of Community Medicine, University of Tulsa, Tulsa, OK, USA. Electronic address: jsavitz@laureateinstitute.org.
Jonathan
J
Savitz
D000328:Adult; D003865:Major Depressive Disorder / Q000097:blood* / Q000000981:diagnostic imaging / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D007736:Kynurenic Acid / Q000097:blood*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000097:blood; D008279:Magnetic Resonance Imaging; D008297:Male; D061212:Memory, Episodic; D011939:Mental Recall / Q000502:physiology*; D008875:Middle Aged; D017378:Quinolinic Acid / Q000097:blood*; D055815:Young Adult
C005045:3-hydroxykynurenine; D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid
Hippocampus; Magnetic resonance imaging; Major depressive disorder; Memory; Quinolinic acid