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Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation
Frontiers in Cellular Neuroscience ( IF 4.2 ) Pub Date : 2020-09-14 , DOI: 10.3389/fncel.2020.558181
Chin Wai Hui , Haley A. Vecchiarelli , Étienne Gervais , Xiao Luo , Félix Michaud , Lisa Scheefhals , Kanchan Bisht , Kaushik Sharma , Lisa Topolnik , Marie-Ève Tremblay

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.



中文翻译:

暴露于母体免疫激活的成年小鼠后代海马齿状回小胶质细胞和突触的性别差异

精神分裂症是一种精神疾病,影响全世界约1%的人类。男性比女性更早,更频繁地被诊断出病,并且男性表现出更明显的负面症状以及更大的灰质减少。我们以前的发现利用精神分裂症的母体免疫激活(mIA)小鼠模型揭示,成年雄性后代中加剧的焦虑样行为和感觉运动门控缺陷与海马齿状回(DG)的小胶质细胞反应性和炎症增加有关。但是,成年雄性和雌性后代都表现出刻板印象和社交能力受损。我们假设,mIA可能导致小胶质细胞修剪活性的性别特异性改变,从而导致DG中的突触连接异常。使用相同的mIA模型,我们在当前的研究中显示了成年后代DG中小胶质细胞和突触的性别特异性差异。具体而言,在暴露于mIA的女性中,小胶质细胞分化簇(CD)68和CD11b的水平升高。发生mIA后,还观察到了兴奋性和抑制性突触密度的性别特异性差异。另外,雄性和雌性的DG颗粒细胞中抑制性突触的音调均增加,而兴奋性突触传递的改变仅发生在具有mIA的女性中。这些发现表明,吞噬和补体途径可能共同导致mIA的突触修剪和神经元功能异常中的性二态性,并可能提出针对性别的治疗靶点,以预防精神分裂症样行为。在暴露于mIA的女性中,小胶质细胞分化簇(CD)68和CD11b的水平增加。发生mIA后,还观察到了兴奋性和抑制性突触密度的性别特异性差异。另外,雄性和雌性的DG颗粒细胞中抑制性突触的音调均增加,而兴奋性突触传递的改变仅发生在具有mIA的女性中。这些发现表明,吞噬和补体途径可能共同导致mIA的突触修剪和神经元功能异常中的性二态性,并可能提出针对性别的治疗靶点,以预防精神分裂症样行为。在暴露于mIA的女性中,小胶质细胞分化簇(CD)68和CD11b的水平增加。发生mIA后,还观察到了兴奋性和抑制性突触密度的性别特异性差异。另外,雄性和雌性的DG颗粒细胞中抑制性突触的音调均增加,而兴奋性突触传递的改变仅发生在具有mIA的女性中。这些发现表明,吞噬和补体途径可能共同导致mIA的突触修剪和神经元功能异常中的性二态性,并可能提出针对性别的治疗靶点,以预防精神分裂症样行为。另外,雄性和雌性的DG颗粒细胞中抑制性突触的音调均增加,而兴奋性突触传递的改变仅发生在具有mIA的女性中。这些发现表明,吞噬和补体途径可能共同导致mIA的突触修剪和神经元功能异常中的性二态性,并可能提出针对性别的治疗靶点,以预防精神分裂症样行为。另外,雄性和雌性的DG颗粒细胞中抑制性突触的音调均增加,而兴奋性突触传递的改变仅发生在具有mIA的女性中。这些发现表明,吞噬和补体途径可能共同导致mIA的突触修剪和神经元功能异常中的性二态性,并可能提出针对性别的治疗靶点,以预防精神分裂症样行为。

更新日期:2020-10-16
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