Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: implications for schizophrenia

We characterized the in vivo and in vitro consequences of reduced expression of Slc1a1 in mice. Heterozygous (HET) Slc1a1+/- mice, which model the hemi-deletion we found in human subjects with schizophrenia, were examined in a series of behavioral, anatomical and biochemical assays. Knockout (KO) mice were also included in the behavioral studies for comparative purposes. Both HET and KO mice exhibited evidence of increased anxiety-like behavior, impaired working memory, decreased exploratory activity and impaired sensorimotor gating, but no changes in overall locomotor activity compared to wildtype (WT) mice. The magnitude of changes was approximately equivalent in the HET and KO mice suggesting a dominant effect of the haploinsufficiency. Whole transcriptome RNA-Seq analysis detected expression changes of genes and pathways involved in cytokine signaling and synaptic functions in both brain and blood of the HET mice compared to WT mice. mRNA profiles of the whole brain and whole blood of young adult wild type (WT) Slc1a1 +/+ and heterozygous (HET) Slc1a1 +/- mice were generated by stranded RNA-seq, with n = 5 per genotype per tissue, using an Illumina NextSeq500.本研究对小鼠中溶质载体家族1成员1（Slc1a1）表达降低所产生的体内（in vivo）与体外（in vitro）效应进行了系统表征。我们以Slc1a1+/-杂合子（Heterozygous, HET）小鼠为研究对象，该模型模拟了我们在精神分裂症人类受试者中发现的半合子缺失，并通过一系列行为学、解剖学与生化实验对其开展检测；为进行对照分析，本研究同时纳入了敲除（Knockout, KO）小鼠的行为学实验数据。与野生型（Wildtype, WT）小鼠相比，杂合子与敲除小鼠均表现出焦虑样行为增多、工作记忆受损、探索活动减少以及感觉运动门控功能受损的表型，但整体运动活动无显著变化。两类小鼠的表型变化幅度基本一致，提示单倍体剂量不足发挥了显性遗传效应。全转录组RNA测序（RNA-Seq）分析显示，相较于野生型小鼠，杂合子小鼠的大脑与血液样本中，参与细胞因子信号传导与突触功能的基因及通路均出现了表达异常。本研究使用Illumina NextSeq500测序平台，通过链特异性RNA测序（stranded RNA-seq）获取了年轻成年野生型Slc1a1 +/+与杂合子Slc1a1 +/-小鼠的全脑及全血mRNA表达谱，每个组织的每个基因型设置5个生物学重复（n=5）。