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.

在包括精神分裂症 (SZ) 在内的各种精神疾病中，已经报道了犬尿氨酸途径 (KP) 代谢的明显异常。犬尿烯酸 (KYNA) 是 KP 的一种神经活性代谢物，在诊断为 SZ 的个体中升高，并且与该疾病中的认知障碍有关。为了进一步了解 KYNA 在 SZ 病因学中的作用，我们开发了一种产前侮辱模型，其中从胚胎日 (ED) 15 到 ED 22 将犬尿氨酸（100 毫克/天）喂给怀孕的 Wistar 大鼠。 由于患病率和严重程度的性别差异已经观察到 SZ，我们目前研究了产前犬尿氨酸暴露对雄性和雌性后代 KP 代谢和空间学习和记忆的影响。具体来说，来自后代的脑组织和血浆（对照：ECon；犬尿氨酸处理：EKyn）在青春期前（产后第 21 天）、青春期（PD 32-35）和成年期（PD 56-85）被收集。在巴恩斯迷宫中测试了不同的成年后代队列，以评估海马体和前额叶皮层介导的学习和记忆。血浆色氨酸、犬尿氨酸和 KYNA 在所有三个年龄的 ECon 和 EKyn 后代之间都没有变化。与 ECon 相比，雄性 EKyn 后代的海马和额叶皮层 KYNA 仅在成年期升高，而成年雌性的脑 KYNA 水平没有变化。雄性 EKyn 后代在获得巴恩斯迷宫和任务中的逆向学习期间显着受损。在雌性 EKyn 后代中，学习和记忆保持相对完整。综合起来，