Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation.

Chin Wai Hui,Haley A Vecchiarelli,Étienne Gervais,Lisa Scheefhals,Kanchan Bisht,Marie-Ève Tremblay,Xiao Luo,Kaushik Sharma,Lisa Topolnik,Félix Michaud

doi:10.3389/fncel.2020.558181

Abstract

Schizophrenia is a psychiatric disorder affecting ∼1% of humans worldwide. It is earlier and more frequently diagnosed in men than woman, and men display more pronounced negative symptoms together with greater gray matter reductions. Our previous findings utilizing a maternal immune activation (mIA) mouse model of schizophrenia revealed exacerbated anxiety-like behavior and sensorimotor gating deficits in adult male offspring that were associated with increased microglial reactivity and inflammation in the hippocampal dentate gyrus (DG). However, both male and female adult offspring displayed stereotypy and impairment of sociability. We hypothesized that mIA may lead to sex-specific alterations in microglial pruning activity, resulting in abnormal synaptic connectivity in the DG. Using the same mIA model, we show in the current study sex-specific differences in microglia and synapses within the DG of adult offspring. Specifically, microglial levels of cluster of differentiation (CD)68 and CD11b were increased in mIA-exposed females. Sex-specific differences in excitatory and inhibitory synapse densities were also observed following mIA. Additionally, inhibitory synaptic tone was increased in DG granule cells of both males and females, while changes in excitatory synaptic transmission occurred only in females with mIA. These findings suggest that phagocytic and complement pathways may together contribute to a sexual dimorphism in synaptic pruning and neuronal dysfunction in mIA, and may propose sex-specific therapeutic targets to prevent schizophrenia-like behaviors.

Highlights

Schizophrenia is a psychiatric disorder that affects ∼1% of humankind
There were baseline sex differences, with females having more excitatory synapses than males (Figure 3E). These data indicate that following maternal immune activation (mIA), there is a dynamic synaptic reorganization taking place in the polymorphic layer (PL), where inhibitory and excitatory synapses both increase in male offspring, and where inhibitory synapses are unchanged while excitatory synapses decrease in female offspring
This study highlights sex differences in microglial phagolysosomal activity, complement system, neuronal health, and excitatory and inhibitory synapse density and activity, in the dentate gyrus (DG) of adult offspring exposed to mIA with polycytidylic acid (poly I):C

Summary

Introduction

Schizophrenia is a psychiatric disorder that affects ∼1% of humankind. It is more frequently diagnosed in men than women; men are more likely to have an earlier age of disease onset and experience more negative symptoms (Mendrek and Mancini-Marïe, 2016). Microglia are required for proper brain development, plasticity and homeostasis (Tian et al, 2017). Their pruning of synapses can be mediated through the complement (C) 3/C1q pathway (Stevens et al, 2007; Paolicelli et al, 2011; Schafer et al, 2012), which may contribute to an inadequate synaptic maintenance when abnormally active in disease (Druart and Le Magueresse, 2019). Our previous work revealed overall sex differences in microglial density, and, utilizing a polyinosinic:polycytidylic acid (poly I:C) mIA mouse model, increased morphological index (soma area/arborization area) and interactions with synapses in the hippocampal dentate gyrus (DG) of adult male offspring, correlating with schizophrenia-like behavioral deficits (Hui et al, 2018)

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