Prenatal Immune Challenge in Mice Leads to Partly Sex-Dependent Behavioral, Microglial, and Molecular Abnormalities Associated with Schizophrenia.

Chin W Hui,Hassan El Hajj,Marie-Ève Tremblay,Giamal N Luheshi,Yvan Remy,Sébastien S Hébert,Lalit K Srivastava,Abygaël St-Pierre

doi:10.3389/fnmol.2018.00013

Abstract

Epidemiological studies revealed that environmental factors comprising prenatal infection are strongly linked to risk for later development of neuropsychiatric disorders such as schizophrenia. Considering strong sex differences in schizophrenia and its increased prevalence in males, we designed a methodological approach to investigate possible sex differences in pathophysiological mechanisms. Prenatal immune challenge was modeled by systemic administration of the viral mimic polyinosinic-polycytidylic acid (Poly I:C) to C57BL/6 mice at embryonic day 9.5. The consequences on behavior, gene expression, and microglia—brain immune cells that are critical for normal development—were characterized in male vs. female offspring at adulthood. The cerebral cortex, hippocampus, and cerebellum, regions where structural and functional alterations were mainly described in schizophrenia patients, were selected for cellular and molecular analyses. Confocal and electron microscopy revealed most pronounced differences in microglial distribution, arborization, cellular stress, and synaptic interactions in the hippocampus of male vs. female offspring exposed to Poly I:C. Sex differences in microglia were also measured under both steady-state and Poly I:C conditions. These microglial alterations were accompanied by behavioral impairment, affecting for instance sensorimotor gating, in males. Consistent with these results, increased expression of genes related to inflammation was measured in cerebral cortex and hippocampus of males challenged with Poly I:C. Overall, these findings suggest that schizophrenia's higher incidence in males might be associated, among other mechanisms, with an increased microglial reactivity to prenatal immune challenges, hence determining disease outcomes into adulthood.

Highlights

Schizophrenia is a chronic and severe psychiatric disorder that is 1.4 times more frequently diagnosed in males than females, over the course of late adolescence or early adulthood (Picchioni and Murray, 2007)
To study further microglial alterations and their possible sex-differences induced by prenatal polycytidylic acid (Poly I):C, extensive morphological analyses were performed in male vs. female adult (P80-P90) offspring exposed to Poly I:C at
The present findings show that Poly I:C-induced prenatal immune challenge at E9.5 triggers behavioral impairments accompanied by exacerbated inflammation, oxidative stress, and microglial alterations, in males

Summary

Introduction

Schizophrenia is a chronic and severe psychiatric disorder that is 1.4 times more frequently diagnosed in males than females, over the course of late adolescence or early adulthood (Picchioni and Murray, 2007). Sex differences in antipsychotic responses were identified, with better improvement of negative symptoms measured in men, and of affective symptoms and cognitive functions in women (Abel et al, 2010). Animal models of maternal immune activation (mIA) using the viral mimic Poly I:C, or other immune stimuli, display neurobehavioral impairments affecting motor control, anxiety, sociability, memory, and sensorimotor gating that are reminiscent of schizophrenia symptoms (Jones et al, 2011; Meyer, 2014). Important insights into the pathophysiology of schizophrenia were provided by mIA models, involving neuroinflammation, oxidative stress, neuronal dysfunction, neurotransmitter imbalance, and neurogenesis, among others mechanisms (Lanté et al, 2007; Meyer et al, 2008; Bitanihirwe et al, 2010; Mattei et al, 2014; Manitz et al, 2016)

Methods

Results

Conclusion