Behavioral Balance in Tryptophan Turmoil: Regional Metabolic Rewiring in Kynurenine Aminotransferase II Knockout Mice

Background: Cognitive, emotional, and social dysfunctions pervade neuropsychiatric disorders; dysregulated tryptophan (Trp)–kynurenine signaling, notably kynurenic acid (KYNA) from kynurenine aminotransferases (KATs), is implicated in Alzheimer’ disease, Parkinson’s disease, depression, and post-traumatic stress disorder (PTSD), among others. In novel CRISPR/Cas9-generated KAT II knockout (aadat-/- aka. 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 (Tyr)–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 (QAA) decreased in cerebellum and brainstem. Such spatially restricted shifts delineate metabolic stress as a core transdiagnostic liability, converging with increased oxidative burden and amplified excitotoxic mechanisms. Conclusion: Here we show kat2 deletion reshapes regional Trp metabolism while reinforcing despair-linked emotional bias, this study highlights novel metabolic signatures as stratification biomarkers. These insights may foster double-hit animal models to dissect the convergence of depression and PTSD, ultimately informing targeted therapeutic approaches.