Comprehensive behavioral analysis of tryptophan 2,3‐dioxygenase (Tdo2) knockout mice

Abstract

Aims: Tryptophan 2,3-dioxygenase (TDO2) is an initial rate-limiting enzyme of the kynurenine (Kyn) pathway in tryptophan (Trp) metabolism. The Trp-degrading enzymes, TDO2 and indoleamine 2,3-dioxygenase, are activated by stress and/or inflammation. Dysregulation of Trp metabolism, which causes shifts in the balance between Kyn and serotonin (5-HT) pathways, is associated with psychiatric and neurological disorders. In genetic studies, single-nucleotide polymorphisms in the TDO2 gene were shown to be involved in psychiatric disorders, such as schizophrenia and depression. It has been reported that targeted deletion of the Tdo2 gene in mice resulted in reduced anxiety-like behavior, enhanced exploratory activity and cognitive performance, and increased levels of Trp and 5-HT in the hippocampus and midbrain. However, the effect of Tdo2 gene deletion on behavioral phenotypeshas not yet been investigated extensively. Materials & Methods:We conducted tests to further examine the behavioral effects of knockout (KO) of Tdo2 in mice.Results: Deletion of Tdo2 resulted in seemingly lower anxiety-like behavior, higher locomotor activity, and abnormal gait pattern in mice, though none of them reached study-wide statistical significance. Tdo2 deficiency had no significant effects on other behaviors, such as prepulse inhibition, and depression-like and social behaviors. In previous studies, we identified "immature dentate gyrus (iDG)" phenotype in the adult dentate gyrus (DG). In this phenotype, almost all neurons are arrested in a pseudoimmature state, with regard to molecular and electrophysiological characteristics. [8][9][10][11] The Tdo2 gene, which has a highly selective expression in the DG, is dramatically reduced in the iDG phenotype. The iDG phenotype has been reported in several strains of mutant mice, including a-CaMKII heterozygous KO mice, Schnurri-2 KO mice, mutant SNAP-25 knock-in mice, and forebrain-specific calcineurin KO mice. These mutant mice exhibited shared behavioral abnormalities including hyperactivity and working memory deficits. [8][9][10][11] Additionally, an iDGlike phenotype was observed postmortem in brains of human patients with schizophrenia and bipolar disorder. 12 This observation suggests the possibility that TDO2 could be involved in the pathogenesis or pathophysiology of certain psychiatric disorders.The role of Tdo2 in the brain has been explored using Tdo2 knockout mice. Concentrations of Trp and 5-HT in the hippocampi of mutant mice were higher than those in the hippocampi of wildtype mice. 13 Lower anxiety-like behavior in open-field and elevated plus-maze tests was observed in Tdo2 KO mice. 13 Deletion of Tdo2 in mice has also been associated with increased exploratory activities and cognitive performance. 14,15 To further investigate the effect of Tdo2 on mouse behavioral phenotypes, we conducted a comprehensive battery of behavioral tests, 16,17 evaluating many distinct behavioral domains, ranging from sensorimotor function to cognitive function. | ME TH ODS | Animals and ...

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

“…In this report, we utilized a comprehensive set of well-defined behavioral tests [31][32][33][34][35][36][37][38] and investigated behavioral phenotypes including the sensorimotor functions and the cognitive functions of the Syngap1 −/+ mice generated by Komiyama et al on a C57BL/6J genetic background.…”

Effects of gintonin-enriched fraction on hippocampal gene expressions

“…Thus, decreased kynurenine metabolites and increased Trp and 5-HT concentrations can lead to a reduction of anxiety in the hippocampus and midbrain for improving search activity and cognitive ability. 32 …”

Comprehensive behavioral analysis of indoleamine 2,3‐dioxygenase knockout mice

“…Normally, the oxidizing ability of TDO2, that is its ability to metabolize tryptophan, is approximately threefold greater than that of IDO1 . Tdo2 deletion disturbs the KP and causes more behavioral alterations, such as lower anxiety‐like behavior and higher locomotor activity under basal conditions, than Ido1 deletion . IDO1 activity is quite low in the absence of immune stimuli, which may underlie the lack of an obvious behavioral phenotype in Ido1 KO mice.…”

“…The perturbation of IDO1 or TDO2 activity, which causes KP imbalance, is also reported to be associated with psychiatric and neurological disorders . In our previous study, we conducted a comprehensive battery of behavioral tests with Tdo2 KO mice, which showed lower anxiety‐like behavior, higher locomotor activity, and abnormal gait patterns than the controls . It has been reported that WT mice under inflammatory conditions show increased anxiety‐like behavior in open field and light/dark transition tests, increased depressive‐like behavior on forced swim and tail suspension tests, and decreased novel object recognition, whereas Ido1 KO mice do not exhibit these behaviors .…”