Cells · 2025
Behavioral Balance in Tryptophan Turmoil: Regional Metabolic Rewiring in Kynurenine Aminotransferase II Knockout Mice.
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Szabó Ágnes, Galla Zsolt, Spekker Eleonóra, Martos Diána, Szűcs Mónika, Fejes-Szabó Annamária, Fehér Ágnes, Takeda Keiko, Ozaki Kinuyo, Inoue Hiromi, Yamamoto Sayo, Monostori Péter, Toldi József, Ono Etsuro, Vécsei László, Tanaka Masaru
Аннотация
BACKGROUND: Cognitive, emotional, and social impairments are pervasive across neuropsychiatric conditions, where alterations in the tryptophan (Trp)-kynurenine pathway and its product kynurenic acid (KYNA) from kynurenine aminotransferases (KATs) have been linked to Alzheimer's disease, Parkinson's disease, depression, and post-traumatic stress disorder. In novel CRISPR/Cas9-engineered KAT II knockout (aadat-/- also known as kat2-/-) mice, we observed despair-linked depression-like behavior with peripheral excitotoxicity and oxidative stress. KAT II's role and its crosstalk with serotonin, indole-pyruvate, and tyrosine-dopamine remain unclear. It is unknown whether deficits extend to cognitive, emotional, motor, and social domains or whether brain tissues mirror peripheral stress.
OBJECTIVES: Delineate domain-wide behaviors, brain oxidative/excitotoxic profiles, and pathway interactions attributable to KAT II.
RESULTS: Behavior was unchanged across strains. kat2-/- deletion remodeled Trp metabolic pathways: 3-hydroxykynurenine increased, xanthurenic acid decreased, KYNA fell in cortex and hippocampus but rose in striatum, quinaldic acid decreased in cerebellum and brainstem. These region-specific changes indicate metabolic stress across the brain and align with higher oxidative load and signs of excitotoxic pressure.
CONCLUSIONS: Here, we show that KAT II deletion reshapes regional Trp metabolism and amplifies oxidative and excitotoxic imbalance. Although domain-wide behavioral measures, spanning cognition, sociability, and motor coordination, remained largely unchanged, these neurochemical alterations signify a latent emotional bias rather than overt depressive-like behavior. This work, therefore, refines prior findings by delineating KAT II-linked biochemical vulnerability as a potential substrate for stress-reactive affective dysregulation.
OBJECTIVES: Delineate domain-wide behaviors, brain oxidative/excitotoxic profiles, and pathway interactions attributable to KAT II.
RESULTS: Behavior was unchanged across strains. kat2-/- deletion remodeled Trp metabolic pathways: 3-hydroxykynurenine increased, xanthurenic acid decreased, KYNA fell in cortex and hippocampus but rose in striatum, quinaldic acid decreased in cerebellum and brainstem. These region-specific changes indicate metabolic stress across the brain and align with higher oxidative load and signs of excitotoxic pressure.
CONCLUSIONS: Here, we show that KAT II deletion reshapes regional Trp metabolism and amplifies oxidative and excitotoxic imbalance. Although domain-wide behavioral measures, spanning cognition, sociability, and motor coordination, remained largely unchanged, these neurochemical alterations signify a latent emotional bias rather than overt depressive-like behavior. This work, therefore, refines prior findings by delineating KAT II-linked biochemical vulnerability as a potential substrate for stress-reactive affective dysregulation.