Association between redox dysregulation and vulnerability to cognitive deficits induced by maternal immune activation

Abstract

Exposure to maternal immune activation (MIA) in utero is a major risk factor for neurodevelopmental disorders, including schizophrenia. However, a proportion of individuals are resilient to developing schizophrenia following exposure to MIA, which has also been reported in animal models of MIA. The molecular mechanisms leading to resilient and vulnerable behavioural phenotypes remain poorly understood, and we currently lack reliable blood biomarkers that predict resilience or vulnerability. Redox dysregulation, caused by an imbalance between oxidative stress and antioxidant defence mechanisms, has recently been predicted to be central to the pathogenesis of schizophrenia. Here, we use a poly(I:C)-induced MIA model of schizophrenia to investigate mechanisms underlying cognitive dysfunction and redox dysregulation in resilient and vulnerable individuals. We show that activity of the antioxidant enzyme superoxide dismutase (SOD) was reduced in the plasma of poly(I:C) offspring with a cognitive deficit, in contrast to individuals with typical cognition during both adolescence and adulthood. However, SOD activity in the hippocampus was not significantly different between vulnerable and resilient offspring. In addition, the lipid peroxidation marker malondialdehyde (MDA) and the pro-inflammatory cytokine IL-6 were not differentially expressed within the hippocampus or plasma of vulnerable poly(I:C) offspring. Our results suggest that reduced plasma SOD activity may be a potential blood biomarker to identify resilience or vulnerability to MIA-induced cognitive deficits. Further research is necessary to determine if reduced antioxidant capacity is present in plasma prior to symptom presentation and to understand if this predicts redox dysregulation in the brain.

Fig. 1. MIA offspring exhibit reduced performance in NOR and can be clustered into resilient and vulnerable groups.

a NOR performance when measured by discrimination index during adolescence and adulthood (n = 23–26/group/age). b Discrimination index according to cluster. c Cluster distribution during adolescence where y axis represents percentage of offspring in each cluster, number on bar describes number of offspring in cluster. d Cluster distribution during adulthood where y axis represents percentage of offspring in each cluster, number on bar describes number of offspring in cluster. CL1=typical memory, CL2=deficit memory, PIC=poly(I:C), PIC-RES=resilient poly(I:C) offspring (CL1), PIC-VULN=vulnerable poly(I:C) offspring (CL2), VEH=all vehicle offspring, VEH (CL1)=vehicle offspring belonging to typical memory cluster, VEH (CL2)=vehicle offspring belonging to deficit cluster. *p < 0.05, ***p < 0.001. #p < 0.05 in Chi-squared test. Data are presented as mean ± SEM.

Fig. 2. Offspring plasma biomarkers according to treatment and cluster membership during adolescence and adulthood.

a IL-6 concentration according to treatment group (n = 8–11/sex/group/age). b IL-6 concentration according to cluster (n = 6–16/cluster/age). c SOD activity according to treatment group (10–13/sex/group/age). d SOD activity according to cluster (n = 11–17/cluster/age). e MDA activity (relative to blank) according to treatment group (n = 9–12/sex/group/age). f MDA activity (relative to blank) according to cluster (n = 8–17/cluster/age). PIC=poly(I:C), PIC-RES=resilient poly(I:C) offspring (CL1), PIC-VULN=vulnerable poly(I:C) offspring (CL2), VEH=all vehicle offspring, VEH (CL1)=vehicle offspring belonging to typical memory cluster. *p ≤ 0.05, **p < 0.01. Data are presented as mean ± SEM.

Fig. 3. Offspring oxidative stress marker activity in the dorsal hippocampus according to treatment group and cluster membership during adolescence and adulthood.

a SOD activity according to treatment group (4–6/sex/group/age). b SOD activity according to cluster (n = 5–9/cluster/age). c MDA activity (relative to blank) according to treatment group (n = 6/sex/group/age). d MDA activity (relative to blank) according to cluster (n = 6–9/cluster/age). PIC=poly(I:C), PIC-RES=resilient poly(I:C) offspring (CL1), PIC-VULN=vulnerable poly(I:C) offspring (CL2), VEH=all vehicle offspring, VEH (CL1)=vehicle offspring belonging to typical memory cluster. *p < 0.05. Data are presented as mean ± SEM.