Borna disease virus phosphoprotein expression affects glial functions in the C6 glioma cells

Borna disease virus (BDV) is a highly neurotropic negative-strand RNA virus that belongs to the Mononegavirales. Many reports demonstrated that natural infection of BDV occurs worldwide in a variety of vertebrate species, suggesting that host range of this virus includes all warm-blooded animals. BDV persistently infects the central nervous system (CNS) of many animal species and causes neurobehavioral disorders resembling autism, such as anxiety, aggression, hyperactivity, abnormal play behavior, and cognitive deficits. We previously reported the generation of transgenic mice expressing BDV phosphoprotein (P) selectively in astrocytes. This transgenic mouse, P-Tg, showed striking neurobehavioral abnormalities resembling those in BDV-infected animals, such as enhanced intermale aggressiveness, hyperactivity and spatial reference memory deficit. To reveal the molecular mechanisms how glial cells induce these abnormalities, we performed microarray analysis using C6 rat glioma cells expressing either GFP (C6-GFP) or BDV P (C6-P). Sixty-eight genes are significantly affected in C6-P cells. The genes, whose products are localized at the extracellular region, were enriched in the differentially expressed genes in C6-P cells. Furthermore, gene ontology analysis revealed an emphasis on genes involved in morphogenesis. It is highly likely that the secretion of astrocyte factors may be widely dysregulated in the P-Tg, leading to the astrocyte hypofunction in the brain.博尔纳病病毒（Borna disease virus, BDV）是一种高度嗜神经性的负链RNA病毒，隶属于单股负链病毒目（Mononegavirales）。已有多项研究报道显示，BDV的自然感染在全球范围内的多种脊椎动物中均有发生，提示该病毒的宿主范围涵盖所有温血动物。BDV可持续感染多种动物的中枢神经系统（CNS），并引发类似自闭症的神经行为障碍，具体表现为焦虑、攻击行为、多动、异常玩耍行为及认知功能缺陷。我们此前曾报道构建了仅在星形胶质细胞中特异性表达BDV磷蛋白（phosphoprotein, P）的转基因小鼠模型P-Tg，该模型小鼠表现出与BDV感染动物相似的显著神经行为异常，包括雄性间攻击行为增强、多动及空间参考记忆缺陷。为揭示胶质细胞诱导此类神经行为异常的分子机制，本研究使用分别表达绿色荧光蛋白（GFP）与BDV P蛋白的C6大鼠胶质瘤细胞（C6-GFP、C6-P）开展了基因芯片（microarray）分析。结果显示，C6-P细胞中共有68个基因的表达发生显著改变，其中编码产物定位于细胞外区域的基因在差异表达基因中显著富集。此外，基因本体论（gene ontology, GO）分析显示，差异表达基因显著富集于形态发生相关的生物学过程。综上，P-Tg小鼠体内星形胶质细胞因子的分泌可能存在广泛失调，进而导致脑组织内星形胶质细胞功能低下。