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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 phenotypes has 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.

Discussion and conclusion: He lack of clear phenotypes in Tdo2KO mice in this study might be due to the absence of stress and inflammatory conditions, which could induce expression of Tdo2 mRNA. Further studies are necessary to elucidate the roles of Tdo2 in behavioral phenotypes related to psychiatric disorders.

SUBMITTER: Hattori S

PROVIDER: S-EPMC7292271 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Hattori Satoko S Takao Keizo K Funakoshi Hiroshi H Miyakawa Tsuyoshi T

Neuropsychopharmacology reports 20180315 2

<h4>Aims</h4>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 ...[more]

PMID: 30106261

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Project description:Aims: Synaptic Ras GTPase-activating protein 1 (SYNGAP1) regulates synaptic plasticity through AMPA receptor trafficking. SYNGAP1 mutations have been found in human patients with intellectual disability (ID) and autism spectrum disorder (ASD). Almost every individual with SYNGAP1-related ID develops epilepsy, and approximately 50% have ASD. SYNGAP1-related ID is estimated to account for at least 1% of ID cases. In mouse models with Syngap1 mutations, strong cognitive and affective dysfunctions have been reported, yet some findings are inconsistent across studies. To further understand the behavioral significance of the SYNGAP1 gene, we assessed various domains of behavior in Syngap1 heterozygous mutant mice using a behavioral test battery.Methods: Male mice with a heterozygous mutation in the Syngap1 gene (Syngap1-/+ mice) created by Seth Grant's group were subjected to a battery of comprehensive behavioral tests, which examined general health, and neurological screens, rotarod, hot plate, open field, light/dark transition, elevated plus maze, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, gait analysis, T-maze, Y-maze, Barnes maze, contextual and cued fear conditioning, and home cage locomotor activity. To control for type I errors due to multiple-hypothesis testing, P-values below the false discovery rate calculated by the Benjamini-Hochberg method were considered as study-wide statistically significant.Results: Syngap1-/+ mice showed increased locomotor activity, decreased prepulse inhibition, and impaired working and reference spatial memory, consistent with preceding studies. Impairment of context fear memory and increased startle reflex in Syngap1 mutant mice could not be reproduced. Significant decreases in sensitivity to painful stimuli and impaired motor function were observed in Syngap1-/+ mice. Decreased anxiety-like behavior and depression-like behavior were noted, although increased locomotor activity is a potential confounding factor of these phenotypes. Increased home cage locomotor activity indicated hyperlocomotor activity not only in specific behavioral test conditions but also in familiar environments.Conclusion: In Syngap1-/+ mice, we could reproduce most of the previously reported cognitive and emotional deficits. The decreased sensitivity to painful stimuli and impaired motor function that we found in Syngap1-/+ mice are consistent with the common characteristics of patients with SYNGAP-related ID. We further confirmed that the Syngap1 heterozygote mouse recapitulates the symptoms of ID and ASD patients.

Dataset Information

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

Publications

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

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