Low levels of kynurenic acid (KYNA) has been linked to mood disorders, including depression, and likely contributes to the pathophysiology of the disorder. In fact, it has been suggested that this neuroprotective metabolite could be used as a biomarker for the diagnosis of depression and treatment response (Erabi et al., 2020). Kynurenine aminotransferase (KAT) activity is likely the root cause of decreased KYNA in depression.
Animal models of depression are key in identifying potential therapeutics and understanding the underlying pathophysiology of depression. In a recent study, Dr. Masaru Tanaka and colleagues developed a knockout mouse model to investigate the effects that KAT II has on depression. In this study, CRISPR/Cas9 was used to create the transgenic animals (kat2-/-). The KAT transgenic animals had signs of depression, in the forced swim test kat2-/- had significantly longer immobility time compared to wild type mice. Additionally, in the open field test kat2-/- mice had shorter ambulation distances, less jumping counts, and less entries overall. Taken together, KAT II deficiency models depression and PTSD.
In this study, tryptophan metabolites were also investigated in plasma and urine. It is not surprising that KAT II knockout mice have decreased levels of KYNA compared to wild type animals both in urine and plasma. However, these transgenic animals also have altered plasma kynurenine, 3-hydroxykynurenine, anthranilic acid, xanthurenic acid, 5-hydroxyanthranilic acid, and indole-3-acetic acid. Additionally, kynurenine 3-monooxygenase enzyme activity was significantly increased in both plasma and urine compared to wild type animals promoting the production of the neurotoxic metabolite 3-HK and likely driving oxidative stress in kat2-/- mice.
This model demonstrates that KAT II deficiency (or decreased activity) plays a role in the pathophysiology of depression and PTSD. KYNA has also been linked to Alzheimer’s disease and cognitive impairment. While the authors noted that there were no signs of cognitive impairment in kat2-/- mice, behavioral studies were conducted on 8-week-old animals; therefore, it will be interesting to see if long-term KAT II deficiency leads to cognitive impairment as well.