Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder
Backgrounds: Memory and emotion are especially vulnerable to psychiatric disorders such as post-traumatic stress disorder (PTSD), which is linked to disruptions in serotonin (5-HT) metabolism. Over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (K...
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2025-01-01
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| Series: | Frontiers in Bioscience-Landmark |
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| Online Access: | https://www.imrpress.com/journal/FBL/30/1/10.31083/FBL25706 |
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| author | Ágnes Szabó Zsolt Galla Eleonóra Spekker Mónika Szűcs Diána Martos Keiko Takeda Kinuyo Ozaki Hiromi Inoue Sayo Yamamoto József Toldi Etsuro Ono László Vécsei Masaru Tanaka |
| author_facet | Ágnes Szabó Zsolt Galla Eleonóra Spekker Mónika Szűcs Diána Martos Keiko Takeda Kinuyo Ozaki Hiromi Inoue Sayo Yamamoto József Toldi Etsuro Ono László Vécsei Masaru Tanaka |
| author_sort | Ágnes Szabó |
| collection | DOAJ |
| description | Backgrounds: Memory and emotion are especially vulnerable to psychiatric disorders such as post-traumatic stress disorder (PTSD), which is linked to disruptions in serotonin (5-HT) metabolism. Over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) metabolic pathway, which generates a variety of bioactive molecules. Dysregulation of KYN metabolism, particularly low levels of kynurenic acid (KYNA), appears to be linked to neuropsychiatric disorders. The majority of KYNA is produced by the aadat (kat2) gene-encoded mitochondrial kynurenine aminotransferase (KAT) isotype 2. Little is known about the consequences of deleting the KYN enzyme gene. Methods: In CRISPR/Cas9-induced aadat knockout (kat2-/-) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and urine of 8-week-old males compared to wild-type mice. Results: Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: antioxidant KYNs, 5-hydroxyindoleacetic acid, and indole-3-acetic acid levels were lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase were lower, but kynurenine 3-monooxygenase was higher; and oxidative stress and excitotoxicity indices were higher. Transgenic mice displayed depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-hydroxykynurenine pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite. Conclusions: This is the first evidence that deleting the aadat gene induces depression-like behaviors uniquely linked to experiences of despair, which appear to be associated with excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in despair-based depression, a better understanding of these complex conditions, and more effective therapeutic strategies by elucidating the relationship between Trp metabolism and PTSD pathogenesis. |
| format | Article |
| id | doaj-art-0dacd24abd0e4c07ad7ab6e85bed2d9a |
| institution | Kabale University |
| issn | 2768-6701 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | IMR Press |
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| series | Frontiers in Bioscience-Landmark |
| spelling | doaj-art-0dacd24abd0e4c07ad7ab6e85bed2d9a2025-01-25T08:55:52ZengIMR PressFrontiers in Bioscience-Landmark2768-67012025-01-013012570610.31083/FBL25706S2768-6701(24)01560-0Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress DisorderÁgnes Szabó0Zsolt Galla1Eleonóra Spekker2Mónika Szűcs3Diána Martos4Keiko Takeda5Kinuyo Ozaki6Hiromi Inoue7Sayo Yamamoto8József Toldi9Etsuro Ono10László Vécsei11Masaru Tanaka12Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725 Szeged, HungaryDepartment of Pediatrics, Albert Szent-Györgyi Faculty of Medicine, University of Szeged, H-6725 Szeged, HungaryHUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Danube Neuroscience Research Laboratory, H-6725 Szeged, HungaryDepartment of Medical Physics and Informatics, Albert Szent-Györgyi Medical School, Faculty of Science and Informatics, University of Szeged, H-6720 Szeged, HungaryHUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Danube Neuroscience Research Laboratory, H-6725 Szeged, HungaryDepartment of Biomedicine, Graduate School of Medical Sciences, Kyushu University, 812-8582 Fukuoka, JapanCenter of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, 812-8582 Fukuoka, JapanCenter of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, 812-8582 Fukuoka, JapanCenter of Biomedical Research, Research Center for Human Disease Modeling, Graduate School of Medical Sciences, Kyushu University, 812-8582 Fukuoka, JapanDepartment of Physiology, Anatomy and Neuroscience, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, HungaryDepartment of Biomedicine, Graduate School of Medical Sciences, Kyushu University, 812-8582 Fukuoka, JapanDepartment of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725 Szeged, HungaryHUN-REN-SZTE Neuroscience Research Group, Hungarian Research Network, University of Szeged (HUN-REN-SZTE), Danube Neuroscience Research Laboratory, H-6725 Szeged, HungaryBackgrounds: Memory and emotion are especially vulnerable to psychiatric disorders such as post-traumatic stress disorder (PTSD), which is linked to disruptions in serotonin (5-HT) metabolism. Over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) metabolic pathway, which generates a variety of bioactive molecules. Dysregulation of KYN metabolism, particularly low levels of kynurenic acid (KYNA), appears to be linked to neuropsychiatric disorders. The majority of KYNA is produced by the aadat (kat2) gene-encoded mitochondrial kynurenine aminotransferase (KAT) isotype 2. Little is known about the consequences of deleting the KYN enzyme gene. Methods: In CRISPR/Cas9-induced aadat knockout (kat2-/-) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and urine of 8-week-old males compared to wild-type mice. Results: Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: antioxidant KYNs, 5-hydroxyindoleacetic acid, and indole-3-acetic acid levels were lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase were lower, but kynurenine 3-monooxygenase was higher; and oxidative stress and excitotoxicity indices were higher. Transgenic mice displayed depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-hydroxykynurenine pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite. Conclusions: This is the first evidence that deleting the aadat gene induces depression-like behaviors uniquely linked to experiences of despair, which appear to be associated with excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in despair-based depression, a better understanding of these complex conditions, and more effective therapeutic strategies by elucidating the relationship between Trp metabolism and PTSD pathogenesis.https://www.imrpress.com/journal/FBL/30/1/10.31083/FBL25706post-traumatic stress disorder (ptsd)depressionanxietytryptophankynureninemicrobiotaoxidative stresstransgenic micetranslational medical researchcrispr/cas9 |
| spellingShingle | Ágnes Szabó Zsolt Galla Eleonóra Spekker Mónika Szűcs Diána Martos Keiko Takeda Kinuyo Ozaki Hiromi Inoue Sayo Yamamoto József Toldi Etsuro Ono László Vécsei Masaru Tanaka Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder Frontiers in Bioscience-Landmark post-traumatic stress disorder (ptsd) depression anxiety tryptophan kynurenine microbiota oxidative stress transgenic mice translational medical research crispr/cas9 |
| title | Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder |
| title_full | Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder |
| title_fullStr | Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder |
| title_full_unstemmed | Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder |
| title_short | Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder |
| title_sort | oxidative and excitatory neurotoxic stresses in crispr cas9 induced kynurenine aminotransferase knockout mice a novel model for despair based depression and post traumatic stress disorder |
| topic | post-traumatic stress disorder (ptsd) depression anxiety tryptophan kynurenine microbiota oxidative stress transgenic mice translational medical research crispr/cas9 |
| url | https://www.imrpress.com/journal/FBL/30/1/10.31083/FBL25706 |
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