Elsevier

Brain, Behavior, and Immunity

Volume 50, November 2015, Pages 115-124
Brain, Behavior, and Immunity

Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory

https://doi.org/10.1016/j.bbi.2015.06.022Get rights and content

Highlights

  • Peripheral immune challenge with LPS impairs novel object recognition (NOR).

  • IDO mediates impaired recognition memory caused by LPS.

  • Direct administration of l-kynurenine recapitulates the effect of LPS.

  • KMO deficient mice are protected from LPS-induced disruption of NOR.

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.

Introduction

Activation of the peripheral innate immune system and the production of proinflammatory cytokines are now recognized as important contributors to neuropsychiatric illnesses, specifically in the development of depressive symptoms including aspects of cognitive impairment (Reichenberg et al., 2001, Dantzer et al., 2008). Depressed patients often exhibit increased plasma levels of proinflammatory cytokines compared to healthy controls including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β (Dantzer et al., 2008, Dowlati et al., 2010). Further, administration of cytokines, like interferon (IFN)-α, for the treatment of some cancers and viral infections has been shown to induce symptoms of major depression in more than half of the patients undergoing treatment (Capuron and Miller, 2004). More recently, the administration of bacterial endotoxin (lipopolysaccharide or LPS) has become a reliable experimental method to activate the peripheral immune system in both human and animal studies to explore the mediators linking a proinflammatory milieu to resultant depressive symptoms. A low dose of endotoxin in healthy human volunteers was sufficient to increase TNF-α and IL-6 plasma levels up to 4 h after administration which coincided with an increase in depressed mood and a decrease in memory functions in short term recall tests (Reichenberg et al., 2001). Furthermore, in rodents, administration of moderate doses of LPS (<1.0 mg/kg) results in a characteristic sickness response including decreased food intake and reduced locomotion which subsides by approximately 12–18 h post-administration followed by the development of depressive-like behaviors measured 24–28 h post-LPS (O’Connor et al., 2009a, O’Connor et al., 2009b, Salazar et al., 2012, Walker et al., 2013).

There is growing evidence implicating the kynurenine pathway (KP) of tryptophan metabolism as a key mediator of inflammation-related depressive symptoms (Fig. 1); (Raison et al., 2010a, Dantzer et al., 2011). The majority of dietary tryptophan is metabolized through the KP, and under certain pathological conditions neurochemically active metabolites can be generated (Schwarcz et al., 2012). During normal homeostatic conditions, the predominantly hepatic enzyme tryptophan 2,3-dioxygenase (TDO) is responsible for the initial step of the kynurenine pathway, metabolizing tryptophan to N-formylkynurenine which is subsequently metabolized to kynurenine. However, during proinflammatory conditions or after experimental administration of LPS, the extra-hepatic enzyme indoleamine 2,3-dioxygenase (IDO) is upregulated both in the periphery and the brain, and increases the production of kynurenine (Andre et al., 2008). Kynurenine can subsequently be metabolized via two distinct routes: via the kynurenine aminotransferases (KAT) yielding kynurenic acid (KYNA) or via kynurenine monooxygenase (KMO), kynureninase (KYNU), and 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) to produce quinolinic acid (QUIN). QUIN acts at N-methyl-d-aspartate (NMDA) receptors as an agonist and in the brain, KMO activity in microglia is the rate limiting step for the generation of QUIN (Schwarcz et al., 2012). KYNA, in addition to acting at NMDA receptors as an antagonist, also has inhibitory activity at the α7 nicotinic acetylcholine receptor (α7nAChR) (Schwarcz et al., 2012). Peripherally produced kynurenine readily crosses the blood brain barrier via large neutral amino acid transporters providing the substrate for the production of these neuroactive metabolites which could result in altered brain function.

Interestingly, cytokine induced depression was associated with reduced levels of tryptophan and increased levels of kynurenine measured in serum (Capuron et al., 2002). Furthermore, concentrations of kynurenine, QUIN and KYNA were increased in the cerebrospinal fluid of patients receiving IFN-α therapy, and QUIN was positively correlated with Montgomery-Asberg Depression Rating Scale scores (Raison et al., 2010b). Similarly, many LPS-induced depressive-like behaviors in mouse models are mediated by IDO (O’Connor et al., 2009a, O’Connor et al., 2009b, Salazar et al., 2012), and while both peripheral immune challenge and disruption of the KP have been independently reported to impair cognitive processes (Haba et al., 2012, Pocivavsek et al., 2012), the mechanistic role of IDO in mediating inflammation-induced cognitive dysfunction has not been investigated.

The novel object recognition task assesses various aspects of learning and memory. Experimental manipulations allow for investigations of encoding, consolidation and retrieval (Ennaceur and Delacour, 1988, Winters and Bussey, 2005). Importantly, the perirhinal cortex, a subdivision of the parahippocampal region, is the primary region responsible for facilitating recognition memory. Lesion studies which ablate the function of the perirhinal cortex have demonstrated that this region is necessary for normal performance of the novel object recognition task (Ennaceur and Aggleton, 1997, Mumby et al., 2002, Norman and Eacott, 2004). Additionally, the entorhinal cortex (also a subdivision of the parahippocampal region), the hippocampus and the medial prefrontal cortex, have all been identified as important regulators of object recognition. Both hippocampus and medial prefrontal cortex (mPFC) appear to be involved in object recognition tasks with a temporal factor (Hammond et al., 2004, Cross et al., 2012). Hammond et al. found that lesions to the hippocampus interfered with object recognition at a long delay (24 h) but not a short delay (5 min) (Hammond et al., 2004). Lesions to the mPFC do not affect a simple object recognition task, however when several objects are presented in succession, lesions to the mPFC interfere with discrimination of recency (i.e. which object did they encounter most recently) (Cross et al., 2012). Here, we employed the novel object recognition test to assess the effect of peripheral immune challenge on performance in a cognitive task. We utilized mice with a targeted deletion of the IDO1 or KMO gene to determine the mechanistic role of inflammation-induced upregulation of IDO1 and neurotoxic kynurenine metabolism on cognitive performance in this task. These data are the first to demonstrate a decrease in cognitive performance induced by peripheral immune challenge which is mediated by IDO1 and downstream neurotoxic kynurenine metabolism.

Section snippets

Mouse housing and treatments

All animal care and use was carried out in accord with the Guide for the Care and Use of Laboratory Animals, 8th edition (NRC) and approved by the Institutional Animal Care and Use Committee. Wild-type control C57BL/6 J (Jax Strain # 000664) mice and indoleamine 2,3 dioxygenase null (IDO−/−; B6.129-Ido1tm1Alm/J, Jax Strain #005867) mice originated from The Jackson Laboratory (Bar Harbor, ME). KMO transgenic mice (Kmotm1a(KOMP)Wtsi) were obtained through the NIH knockout mouse program, University

Indoleamine 2,3-dioxygenase 1 mediates a deficit in novel object recognition following peripheral immune challenge

We and others have previously demonstrated that IDO mediates many of the depressive-like behaviors that develop following peripheral immune activation (O’Connor et al., 2009a, O’Connor et al., 2009b, Salazar et al., 2012), but its mechanistic role in mediating inflammation-induced cognitive deficits has not been explored. Peripheral administration of LPS induced a deficit in novel object recognition in WT mice as indicated by a significant decrease in their discrimination index (Fig. 2B;

Discussion

The aim of the present study was to determine if activation of the peripheral innate immune response was sufficient to induce a deficit in cognitive function relevant to depressive symptomology and if IDO-dependent kynurenine metabolism is an important pathogenic mediator. Consistent with our previous findings, peripheral challenge with LPS induced a deficit in novel object recognition memory which was mediated by IDO, the rate-limiting enzyme of the kynurenine pathway (Fig. 1). In the absence

Conflict of interest

None of the authors have any conflicts of interest to disclose.

Financial support

This research was supported by Grant Nos. R01-MH090127 and P30-MH089868 from the National Institute of Mental Health, the Norman Hackerman Advanced Research Program and Award Number UL1TR001120 from the National Center for Advancing Translational Sciences. The Kmo mouse model used for this research project was obtained from the KOMP Repository www.komp.org, a NCRR-NIH supported mouse strain repository (U42-RR024244). ES cells from which this mouse was generated were created by the CSD

Role of funding source

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH or NCATS.

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