Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice

Ágnes Szabó; Eleonóra Spekker; Mónika Szűcs; Keiko Takeda; Kinuyo Ozaki; Hiromi Inoue; Sayo Yamamoto; József Toldi; Etsuro Ono; László Vécsei; Masaru Tanaka

doi:10.20944/preprints202308.0094.v4

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preprints.org > medicine and pharmacology > neuroscience and neurology > doi: 10.20944/preprints202308.0094.v4

Preprint Article Version 4 Preserved in Portico This version is not peer-reviewed

Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice

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These authors contributed equally to this work.

Version 1 : Received: 31 July 2023 / Approved: 1 August 2023 / Online: 2 August 2023 (05:15:41 CEST)
Version 2 : Received: 14 September 2023 / Approved: 14 September 2023 / Online: 15 September 2023 (05:36:43 CEST)
Version 3 : Received: 20 September 2023 / Approved: 21 September 2023 / Online: 22 September 2023 (05:03:17 CEST)
Version 4 : Received: 30 September 2023 / Approved: 30 September 2023 / Online: 30 September 2023 (10:34:01 CEST)
Version 5 : Received: 3 May 2024 / Approved: 4 May 2024 / Online: 7 May 2024 (09:27:50 CEST)

How to cite: Szabó, Á.; Spekker, E.; Szűcs, M.; Takeda, K.; Ozaki, K.; Inoue, H.; Yamamoto, S.; Toldi, J.; Ono, E.; Vécsei, L.; Tanaka, M. Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice. Preprints 2023, 2023080094. https://doi.org/10.20944/preprints202308.0094.v4 Szabó, Á.; Spekker, E.; Szűcs, M.; Takeda, K.; Ozaki, K.; Inoue, H.; Yamamoto, S.; Toldi, J.; Ono, E.; Vécsei, L.; Tanaka, M. Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice. Preprints 2023, 2023080094. https://doi.org/10.20944/preprints202308.0094.v4

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MDPI and ACS Style

Szabó, Á.; Spekker, E.; Szűcs, M.; Takeda, K.; Ozaki, K.; Inoue, H.; Yamamoto, S.; Toldi, J.; Ono, E.; Vécsei, L.; Tanaka, M. Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice. Preprints 2023, 2023080094. https://doi.org/10.20944/preprints202308.0094.v4

APA Style

Szabó, Á., Spekker, E., Szűcs, M., Takeda, K., Ozaki, K., Inoue, H., Yamamoto, S., Toldi, J., Ono, E., Vécsei, L., & Tanaka, M. (2023). Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice. Preprints. https://doi.org/10.20944/preprints202308.0094.v4

Chicago/Turabian Style

Szabó, Á., László Vécsei and Masaru Tanaka. 2023 "Exploring the Neurobiological Roots of Emotional Behavior in Tryptophan Metabolism: Insights from Novel Kynurenine Aminotransferase Knockout Mice" Preprints. https://doi.org/10.20944/preprints202308.0094.v4

Abstract

Memory and emotion, fundamental components of our mental existence, are highly vulnerable to psychiatric disorders like post-traumatic stress disorder (PTSD). This condition has been linked to serotonin (5-HT) metabolism disruptions. Over 95% of the 5-HT precursor tryptophan (Trp) is metabolized through the Trp-kynurenine (KYN) metabolic pathway, but little is known about its role in behavior. Kynurenine aminotransferases are responsible for the production of the Trp-KYN metabolite kynurenic acid. The gene aadat codes for mitochondrial kynurenine aminotransferase isotype 2. We generated CRISPR/Cas9-induced aadat knockout (kat2−/−) mice to examine the consequence of the gene deletion on negative valence in emotion, memory, and motor function in males 8 weeks of age and compared them to their wild-type counterparts. The forced swim test showed increased depression-like behaviors in transgenic mice. Anxiety and memory tests showed no significant differences. The transgenic mice had fewer center field and corner entries, shorter ambulation distances, and fewer jumping counts in the open field test. Overall, the transgenic mice exhibit depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits. Here we present the first evidence that the deletion of the aadat gene triggers depression-like behaviors, uniquely associated with despair experience rather than adverse-conditioned memory. These findings have profound implications, opening avenues for further exploration into the main causes of experience-based depression linked to despair. This investigation has the potential to advance our understanding of these complex conditions and pave the way for improved therapeutic strategies by elucidating the relationship between Trp metabolism and the pathogenesis of PTSD.

Keywords

posttraumatic stress disorder (PTSD); depression; anxiety; memory; tryptophan; serotonin (5-HT); kynurenine; transaminases; conversion disorder; experimental animal models

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Received: 30 September 2023
Commenter: Masaru Tanaka
Commenter's Conflict of Interests: Author

Comment: The new version has been revised based on the suggestions of reviewers.

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