Exposure to elevated embryonic kynurenine in rats: Sex-dependent learning and memory impairments in adult offspring

• Published in: Neurobiology of learning and memory Vol. 174; p. 107282
• Main Authors: Buck, Silas A., Baratta, Annalisa M., Pocivavsek, Ana
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2020
• Subjects: Barnes maze; Hippocampus; Kynurenic acid; Learning and memory; Prefrontal cortex; Tryptophan; Learning and memory; KYNA; KP; SZ; Tryptophan; Prefrontal cortex; KMO; α7nACh; KAT II; PD; NMDA; Kynurenic acid; Barnes maze; EKyn; ECon; Hippocampus; ED
• ISSN: 1074-7427; 1095-9564
• DOI: 10.1016/j.nlm.2020.107282

•Kynurenine-laced food was fed to rat dams (EKyn) during the last week of gestation.•Only male EKyn offspring had elevated brain kynurenic acid during adulthood.•Male EKyn offspring have significant impairments in learning and memory. Distinct abnormalities in kynurenine pathway (KP) metabolism have been reported in various psychiatric disorders, including schizophrenia (SZ). Kynurenic acid (KYNA), a neuroactive metabolite of the KP, is elevated in individuals diagnosed with SZ and has been linked to cognitive impairments seen in the disorder. To further understand the role of KYNA in SZ etiology, we developed a prenatal insult model where kynurenine (100 mg/day) is fed to pregnant Wistar rats from embryonic day (ED) 15 to ED 22. As sex differences in the prevalence and severity of SZ have been observed, we presently investigated the impact of prenatal kynurenine exposure on KP metabolism and spatial learning and memory in male and female offspring. Specifically, brain tissue and plasma from offspring (control: ECon; kynurenine-treated: EKyn) in prepuberty (postnatal day (PD) 21), adolescence (PD 32–35), and adulthood (PD 56–85) were collected. Separate cohorts of adult offspring were tested in the Barnes maze to assess hippocampus- and prefrontal cortex-mediated learning and memory. Plasma tryptophan, kynurenine, and KYNA were unchanged between ECon and EKyn offspring across all three ages. Hippocampal and frontal cortex KYNA were elevated in male EKyn offspring only in adulthood, compared to ECon, while brain KYNA levels were unchanged in adult females. Male EKyn offspring were significantly impaired during acquisition of the Barnes maze and during reversal learning in the task. In female EKyn offspring, learning and memory remained relatively intact. Taken together, our data demonstrate that exposure to elevated kynurenine during the last week of gestation results in intriguing sex differences and further support the EKyn model as an attractive tool to study the pathophysiology of schizophrenia.