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

Hirata, Noriko; Shoji, Hirotaka; Funakoshi, Hiroshi; Miyakawa, Tsuyoshi

doi:10.1002/npr2.12019

Cited by 12 publications

(9 citation statements)

References 37 publications

(51 reference statements)

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

Nakajima

Takao

Hattori

et al. 2019

Neuropsychopharm Rep

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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.

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Section: Introductionmentioning

confidence: 99%

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

Nakajima

Takao

Hattori

et al. 2019

Neuropsychopharm Rep

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“…Nevertheless, reviewing such data may raise interest to study the inflammatory component of depression by pharmacological and/or genetic manipulation of either the ECS or the KP. Selective exogenous cannabinoids [ 170 , 171 ] and enzyme inhibitors of the KP as well as CBR and KP enzyme knock-out animals are available and widely used to study the function of the ECS and KP [ 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 ]. Applying these tools may reveal the response of each system to one another when manipulated in inflammatory-induced depression.…”

Section: Discussionmentioning

confidence: 99%

Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid System and the Kynurenine Pathway in Depression

Zádor

Joca

Nagy-Grócz

et al. 2021

IJMS

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Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.

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“…Furthermore, Bacille Calmette-Guérin (BCG) elicited proinflammatory cytokines, but BCG-induced depressive-like behavior was not induced in ido1 -/-knockout mice [68]. However, another study reported that ido1 -/-knockout mice did not exhibit any significantly diferent behavior, compared to the wild type, in comprehensive behavioral assessments including the domain of cognitive function, negative valance system, motor function, social interaction, and pain sensitivity [69]. Ido2 -/-knockout mice increased exploratory activity during light phase [62].…”

Section: Figurementioning

confidence: 99%

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan-Kynurenine Metabolic System

Tanaka¹,

Szabó²,

Spekker³

et al. 2022

Preprint

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Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently growing number of preclinical studies has revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among other. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to development of pathological conditions including neurological and psychiatric disorders. This narrative review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.

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

Abstract: Ido1 KO mice did not show any clear behavioral abnormalities under normal conditions. Further studies may be necessary to investigate their behavioral phenotype under inflammatory conditions due to their known roles in inflammation.

Cited by 12 publications

References 37 publications

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice

Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid System and the Kynurenine Pathway in Depression

Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan-Kynurenine Metabolic System

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