Szabó Ágnes, Galla Zsolt, Spekker Eleonóra, Szűcs Mónika, Martos Diána, Takeda Keiko, Ozaki Kinuyo, Inoue Hiromi, Yamamoto Sayo, Toldi József, Ono Etsuro, Vécsei László, Tanaka Masaru
Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, H-6725 Szeged, Hungary.
Doctoral School of Clinical Medicine, University of Szeged, H-6720 Szeged, Hungary.
Front Biosci (Landmark Ed). 2025 Jan 20;30(1):25706. doi: 10.31083/FBL25706.
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 (kat2) gene-encoded mitochondrial kynurenine aminotransferase (KAT) isotype 2. Little is known about the consequences of deleting the KYN enzyme gene.
In CRISPR/Cas9-induced knockout () 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.
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.
This is the first evidence that deleting the 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.
记忆和情绪特别容易受到诸如创伤后应激障碍（PTSD）等精神疾病的影响，创伤后应激障碍与血清素（5-羟色胺，5-HT）代谢紊乱有关。超过90%的5-羟色胺前体色氨酸（Trp）通过色氨酸-犬尿氨酸（KYN）代谢途径进行代谢，该途径会产生多种生物活性分子。犬尿氨酸代谢失调，尤其是犬尿喹啉酸（KYNA）水平较低，似乎与神经精神疾病有关。大部分的犬尿喹啉酸是由（kat2）基因编码的线粒体犬尿氨酸转氨酶（KAT）同工型2产生的。关于删除犬尿氨酸酶基因的后果知之甚少。
在CRISPR/Cas9诱导的基因敲除（）小鼠中，我们研究了与野生型小鼠相比，8周龄雄性小鼠在情绪、记忆、运动功能、色氨酸及其代谢物水平、血浆和尿液中的酶活性方面的影响。
转基因小鼠在强迫游泳试验中表现出更多的抑郁样行为，但在悬尾试验、焦虑试验或记忆试验中则没有。在旷场试验中，它们进入中央区域和角落的次数也更少，行走距离更短，跳跃次数更少。血浆代谢物水平总体上与尿液中的一致：抗氧化性犬尿氨酸、5-羟吲哚乙酸和吲哚-3-乙酸水平较低；犬尿氨酸转氨酶、犬尿氨酸酶和单胺氧化酶/醛脱氢酶的酶活性较低，但犬尿氨酸3-单加氧酶活性较高；氧化应激和兴奋性毒性指数较高。转基因小鼠在习得性无助模型中表现出抑郁样行为、情感淡漠和运动缺陷，同时犬尿喹啉酸减少，色氨酸代谢向犬尿氨酸-3-羟基犬尿氨酸途径转变，肠道微生物色氨酸-吲哚途径代谢物部分减少。
这是首个证据表明，删除基因会引发与绝望经历独特相关的抑郁样行为，这似乎与兴奋性神经毒性和氧化应激有关。这可能会促成一种基于绝望的抑郁症双打击临床前模型的开发，通过阐明色氨酸代谢与创伤后应激障碍发病机制之间的关系，更好地理解这些复杂病症，并制定更有效的治疗策略。
