Kato T, Abe Y, Hirokawa S, Iwakura Y, Mizuno M, Namba H, Nawa H
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Niigata 951-8585, Japan.
Curr Mol Med. 2015;15(3):222-36. doi: 10.2174/1566524015666150330143300.
Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 μg/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner.
神经调节蛋白-1（NRG1）是一种公认的精神分裂症风险基因，常与该疾病的神经发育假说相关。NRG1基因的可变剪接和蛋白水解加工产生了30多种结构变体；然而，各个变体的神经病理学作用仍有待确定。基于精神分裂症的神经发育假说，我们给新生小鼠注射了eNRG1（0.1~1.0μg/g），它是所有剪接NRG1变体共有的核心表皮生长因子样（EGF）结构域，并将它们的行为表现与用完全成熟形式的1型NRG1变体攻击的小鼠进行比较。在新生阶段，从外周给予的重组eNRG1蛋白穿过血脑屏障并激活脑中的受体（ErbB4）。在成年小鼠中，接受最高剂量eNRG1的小鼠表现出较低的运动活性以及前脉冲抑制和音调依赖性恐惧学习缺陷，尽管eNRG1处理的小鼠听力下降可能解释了这些行为缺陷。新生期eNRG1处理还以eNRG1剂量依赖性方式显著增强了MK-801驱动的运动活性。同时，eNRG1处理增强了MK-801驱动的c-Fos诱导，并降低了成年大脑中NMDA受体亚基的免疫反应性。相比之下，新生期用相同摩尔剂量的完全成熟形式的1型NRG1处理的小鼠对MK-801没有表现出超敏反应。然而，两种动物模型对甲基苯丙胺都表现出相似的超敏反应。总体而言，我们的研究结果表明，神经发育过程中外周NRG1信号异常以NRG1亚型依赖性方式改变后期行为特征和听觉功能。
