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Functional Impairments in Learning and Signal Propagation Following Prenatal Kynurenine Treatment in Mice

Sarah Beggiato,P. Brown,Snežana Milosavljević,Marian A. R. Thomas,Maria V. Piroli,K. V. Sathyasaikumar,F. Notarangelo,R. Schwarcz,Ana Pocivavsek

Published 2025 in European Journal of Neuroscience

ABSTRACT

The levels of kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of tryptophan degradation, are elevated in the brain of persons with schizophrenia (SZ) and may be linked to cognitive dysfunctions in the disease. Studies in rats indicate that abnormally high fetal brain KYNA may play a pathophysiologically significant role in this context (“EKyn model”). Here, we fed pregnant C57Bl/6J mice with the immediate KYNA precursor kynurenine (10 mg or 30 mg/day; EKyn) or with control chow (ECon) from embryonic day (ED) 11 to ED 18 and assessed offspring postnatally both functionally and biochemically. In adulthood, male, but not female, EKyn mice showed significant impairments in spatial and reversal learning. Moreover, ex vivo recording of evoked local field potentials in coronal brain slices revealed a longer contralateral response latency in EKyn than in ECon animals, suggesting impaired white matter function. However, plasma and brain levels of KYNA and of another KP metabolite, 3‐hydroxykynurenine, did not differ between groups on postnatal day (PD) 21, on PD 35 (adolescence), or in adulthood (PD 56–75). Separate mice were fed prenatally with 4‐chloro‐kynurenine (20 mg/day), which is converted to the selective NMDA receptor antagonist 7‐chloro‐KYNA in vivo. Offspring did not show electrophysiological impairments in adulthood, indicating that NMDA receptors in the fetal brain were not the sole cause of functional deficits of EKyn mice later in life. The implications of these experiments for the study of psychiatric symptoms, as well as the unexpected differences between rats and mice, are discussed.

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