Voelcker Academy

Research Symposium 2011


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Rebecca Garcia

Effect of Kynurenine Pathway Dysregulation on Novel Object Preference

Rebecca Garcia

Mentor(s): Jason O’Connor, Ph.D

Tryptophan, an essential amino acid, is the metabolic precursor for serotonin, a neurotransmitter targeted by many antidepressants. However, more than 95% of dietary tryptophan is oxidatively degraded through the kynurenine pathway (KP) by tryptophan 2,3-dioxygenase (TDO). Indoleamine 2,3-dioxygenase (IDO) also degrades tryptophan into kynurenine in negligible amounts under normal conditions; however, during inflammation, cytokines such as interferon-γ and tumor necrosis factor-α increase the amount of IDO that metabolizes tryptophan. Kynurenine is metabolized into the neuroprotective NMDA receptor antagonist, kynurenic acid (KA) or into the neurotoxic NMDA receptor agonist, quinolinic acid (QA), by kynurenine 3-monooxygenase (KMO) and other enzymes. During my time in the lab, I conducted two experiments; both focused on assessing the roles of kynurenine and the two neuroactive metabolites on cognition and recognition memory via the Novel Object Recognition (NOR) task. In experiment 1, 8 wild-type (WT) mice were treated with either saline or kynurenine 30 minutes prior to training with two identical objects. 24 hours after training the mice went through testing, in which one of the familiar objects was replaced by a novel object. Control mice (WT treated with saline) spent 69% percent of their time exploring the novel object, while WT mice treated with kynurenine demonstrated significant reduction in time spent exploring the novel object. This suggests that increasing metabolism through the KP may contribute to cognitive dysfunction. In experiment 2, 18 KMO -/- and 19 WT mice were treated with either saline or lipopolysaccharides (LPS), a component of the outer membrane of gram negative bacteria, which induces an inflammatory response including the production of cytokines. 24 hours after treatment, the mice underwent training, and 48 hours after treatment they were tested with the novel object. Experiment 2 is currently in progress; however, we predict that WT mice treated with saline, KMO -/- saline, and KMO -/- LPS mice will not display cognitive dysfunction, as global deletion of KMO should prevent the neurotoxic QA from being produced. The WT mice treated with LPS are predicted to demonstrate cognitive dysfunction, as inflammation would induce the metabolic breakdown of kynurenine into neurotoxic QA.

Collaborators: Rebecca Garcia, Jillian Heisler, Jason O’Connor