title: Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.
abstract: Cognitive dysfunction in depression is a prevalent and debilitating symptom that is poorly treated by the currently available pharmacotherapies. Research over the past decade has provided evidence for proinflammatory involvement in the neurobiology of depressive disorders and symptoms associated with these disorders, including aspects of memory dysfunction. Recent clinical studies implicate inflammation-related changes in kynurenine metabolism as a potential pathogenic factor in the development of a range of depressive symptoms, including deficits in cognition and memory. Additionally, preclinical work has demonstrated a number of mood-related depressive-like behaviors to be dependent on indoleamine 2,3-dioxygenase-1 (IDO1), the inflammation-induced rate-limiting enzyme of the kynurenine pathway. Here, we demonstrate in a mouse model, that peripheral administration of endotoxin induced a deficit in recognition memory. Mice deficient in IDO were protected from cognitive impairment. Furthermore, endotoxin-induced inflammation increased kynurenine metabolism within the perirhinal/entorhinal cortices, brain regions which have been implicated in recognition memory. A single peripheral injection of kynurenine, the metabolic product of IDO1, was sufficient to induce a deficit in recognition memory in both control and IDO null mice. Finally, kynurenine monooxygenase (KMO) deficient mice were also protected from inflammation-induced deficits on novel object recognition. These data implicate IDO-dependent neurotoxic kynurenine metabolism as a pathogenic factor for cognitive dysfunction in inflammation-induced depressive disorders and a potential novel target for the treatment of these disorders.
authors.affiliation: Department of Pharmacology and the Center for Biomedical Neuroscience in the School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States. Electronic address: HeislerJ@uthscsa.edu.
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Heisler
authors.affiliation: Department of Pharmacology and the Center for Biomedical Neuroscience in the School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States; Audie L. Murphy VA Hospital, South Texas Veterans Health Care System, San Antonio, TX 78229, United States. Electronic address: oconnorj@uthscsa.edu.
authors.forename: Jason C
authors.initials: JC
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003863:Depression / Q000139:chemically induced / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007737:Kynurenine / Q000008:administration & dosage* / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020534:Parahippocampal Gyrus / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D007737:Kynurenine
keywords: Behavior; Indoleamine 2,3-dioxygenase; Kynurenine; Kynurenine monooxygenase; Mouse; Neuroinflammation; Neuropsychiatric symptom; Novel object recognition; Perirhinal cortex; Recognition memory