Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
Department of Psychiatry, Nara Medical University School of Medicine, Nara, Japan.
Brain Behav Immun. 2017 Mar;61:375-385. doi: 10.1016/j.bbi.2017.01.003. Epub 2017 Jan 10.
Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.
多项研究表明，神经调节蛋白（NRGs）参与了大脑功能和精神疾病。尽管 NRGs 被认为是神经元或星形胶质细胞衍生的分子，但我们的研究表明，小胶质细胞也表达 NRGs，其在活化的小胶质细胞中的水平显著增加。先前的研究表明，自闭症谱系障碍（ASD）患者的大脑中存在小胶质细胞的激活。因此，我们在多种被认为是 ASD 模型的小鼠品系中研究了小胶质细胞 NRG mRNA 的表达。有趣的是，BTBR 和社交隔离的小鼠中小胶质细胞 NRG 的表达显著增加，而母体免疫激活（MIA）小鼠与对照组的 NRG 表达相同。此外，我们观察到在小鼠中，小胶质细胞中 NRG 的表达与外周血单核细胞（PBMC）之间呈正相关，这表明人类 PBMC 中 NRG 的表达可能反映了人类大脑中小胶质细胞衍生的 NRG 的表达。为了将这些发现转化为临床精神病学的应用，我们在 ASD 患者的临床可用 PBMC 中测量了 NRG1 剪接变异体的表达水平。PBMC 中 NRG1 型 III 的表达水平与 ASD 儿童的社会交往障碍呈正相关（使用自闭症诊断访谈修订版测试：ADI-R 进行评估）。这些发现表明，免疫细胞衍生的 NRGs 可能与 ASD 等精神疾病的病理生物学有关。
