Neuropathogenic abnormalities in transgenic mice expressing transcription factors of neurotropic viruses in the central nervous system

为了评估嗜神经病毒转录因子的神经致病性，我们培育了几个转基因小鼠系。伪狂犬病毒（PRV）在其自然宿主以外的动物中感染，由于感染周围神经元并随后感染大脑，几乎总是在中枢神经系统中引起致命疾病。为了研究PRV的即时早期蛋白（IE180）在神经致病性中的作用，我们在四环素调控系统（et- off system）中产生了表达IE180的转基因小鼠系。转基因小鼠表现出步态共济失调、震颤和运动失调等小脑症状。在转基因小鼠中，小脑的组织病理学表现为层形成失败和小脑大小缩小。虽然在所有组织中都检测到IE180转录本，但在除小脑外的组织中未观察到组织学异常。这些发现表明，IE180影响小鼠小脑发育的基因级联表达。博纳病病毒感染会导致一系列的行为缺陷。为了研究BDV p24在神经致病性中的作用，我们在星形胶质细胞中产生了表达p24的转基因小鼠系。转基因小鼠表现出雄性间攻击性增强和空间学习异常。转基因小鼠海马和小脑脑源性神经营养因子和突触素明显减少。这些发现表明p24在星形胶质细胞中的表达和积累会造成神经发育障碍。

To assess the neuropathogenic potentials of transcription factors of neurotropic viruses, we have generated several transgenic mouse lines.Pseudorabies virus (PRV) infection in animals other than its natural host almost always gives rise to fatal diseases in the central nervous system as a result of infection of peripheral neurons and subsequent to the brain. To study the role of immediate-early protein (IE180) of PRV in neuropathogenicity, we have generated transgenic mouse lines expressing IE180 in a tetracycline-regulated system (Tet-Off System). The transgenic mice showed cerebellar symptoms such as ataxic gait, tremor and motor discoordination. In the transgenic mice, histopathology of the cerebellum was remarkable for a failure of layer formation and reduced cerebellum sizes. Although the IE180 transcripts were detected in all tissues, no histological abnormality was observed in the tissues other than cerebellum. These findings suggest that IE180 affects the cascade of gene expression for development of the murine cerebellum.Borna disease virus infection causes a spectrum of behavioral deficits. To study the role of p24 of BDV in neuropathogenicity, we have generated transgenic mouse lines expressing p24 in astrocytes. The transgenic mice showed enhanced intermale aggressiveness and abnormalities in spatial learning. In the transgenic mice, brain-derived neurotrophic factor and synaptophysin were markedly decreased in hippocampus and cerebellum. These findings suggest that expression and accumulation of p24 in astrocytes creates neurodevelopmental disturbances.