¹Fujita Health University Graduate School of Medical Sciences, Department of Regulatory Science for Evaluation and Development of Pharmaceuticals and Devices, Toyoake, Japan, ²Fujita Health University, International Center for Brain Science (ICBS), Toyoake, Japan, ³Fujita Health University Graduate School of Medical Sciences, Department of Advanced Diagnostic System Development, Toyoake, Japan, ⁴College of Pharmacy, Kangwon National University, Neuropsychopharmacology and Toxicology Program, BK21 PLUS Project, Chunchon, Korea, Republic of, ⁵Fujita Health University Graduate School of Medical Science, Laboratory of Health and Medical Science Innovation (HMSI), Toyoake, Japan

Background: Maternal immune activation (MIA) is recognized as one of the significant environmental risk factors for neuropsychiatric disorders such as schizophrenia in adult offspring. However, the pathophysiological mechanisms remain unknown.

Aims & Objectives: The tryptophan (TRP)-kynurenine (KYN) pathway, influenced by inflammation, may be implicated in the pathophysiology of neuropsychiatric disorders. We investigated whether abnormal behaviors in adult offspring could be induced by MIA through alterations in the TRP-KYN pathway.

Method: As maternal immune activation, pregnant female mice on E12.5 were injected intraperitoneally (i.p.) with polyI:C (20 mg/kg) .Their offspring were subjected to behavioural test. The placenta and fetal brain of mouse 3 h after polyI:C-treatment were collected and measured IL6. The metabolites of the TRP-KYN pathway and ROS levels in the placenta and fetal brain were measured 24 h after polyI:C-treatment.

Results: MIA increased not only IL-6 expression in the placenta but also reactive oxygen species (ROS) levels in both the placenta and fetal brain and disrupted cortical layering in the fetal brain. We observed increased levels of 3-hydroxykynurenine (3-HK), a metabolite with oxidative stress properties, in both the placenta and fetal brain. In the knockout mice of kynurenine 3-monooxygenase (KMO), the enzyme responsible for 3-HK production, MIA failed to induce the abnormal behaviors in adult offspring. Notably, RO-618048, a KMO inhibitor that does not cross the blood-brain barrier (BBB), also blocked MIA-induced abnormal behaviors in adult offspring, reduced not only increased IL-6 expression in the placenta but also ROS levels in both the placenta and fetal brain, and prevented abnormal cortical development in the fetal brain.

Discussion & Conclusions: These findings suggest that MIA-induced abnormal behaviors in adult offspring may result from the increase in 3-HK levels through activation of KMO. Therefore, KMO is an attractive target for the prevention of neuropsychiatric disorders associated with MIA.