The cerebellar lesions of bovine spongiform encephalopathy (BSE)‐infected guinea pigs were characterized as severe atrophy of the cerebellar cortex associated with the loss of granule cells, decrease in the width of the molecular layer, and intense protease‐resistant prion protein (PrPSc) accumulations that are similar to cerebellar lesions in kuru and the VV2 type of sporadic Creutzfeldt‐Jakob disease. The aim of this study is to assess the relationships between the distribution and localization of PrPSc and synapses expressing neurotransmitter transporters in order to reveal the pathogenesis of the disease. We used cell‐type‐specific immunohistochemical makers recognizing glutamatergic and γ‐aminobutylic acid (GABA)ergic terminals to identify terminals impaired with PrPSc accumulations. The distribution of PrPSc accumulations and immunoreactivity of synaptic vesicles were studied throughout the neuroanatomical pathways in cerebellar lesions. Time course study demonstrated that PrPSc accumulation showed a tendency to spread from granular layer to molecular layer. The immunoreactivity of vesicular glutamate transporter 1 (VGluT1) was localized in axon terminals of cerebellar granule cells, and decreased in association with the severity of PrPSc accumulations and loss of granule cells. Immunoreactivities of vesicular glutamate transporter 2 (VGluT2) and vesicular GABA transporter (VGAT) that exist in axon terminals of inferior olivary neurons and GABAergic synapses of Purkinje cells, respectively, were preserved well in these lesions. In brainstem, VGluT1 immunoreactivity decreased selectively in pontine nuclei that are a component of the pontocerebellar pathway, although other neurotransmitter immunoreactivities were preserved well. Our findings suggest that the selective loss of VGluT1‐immunoreactive synapses subsequent to PrPSc accumulations can contribute to the pathogenesis of cerebellar lesions of BSE‐infected guinea pigs.

中文翻译：

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选择性神经元脆弱性与感染牛海绵状脑病 (BSE) 朊病毒的豚鼠的小脑病变有关：免疫组织化学和电子显微镜研究

牛海绵状脑病 (BSE) 感染豚鼠的小脑病变的特征是小脑皮质严重萎缩，伴有颗粒细胞丢失、分子层宽度减小和强烈的蛋白酶抗性朊病毒蛋白 (PrPSc)类似于库鲁小脑病变和散发性克雅氏病 VV2 型的积聚。本研究的目的是评估 PrPSc 的分布和定位与表达神经递质转运蛋白的突触之间的关系，以揭示该疾病的发病机制。我们使用识别谷氨酸能和 γ-氨基丁酸 (GABA) 能末端的细胞类型特异性免疫组织化学标记来识别因 PrPSc 积累受损的末端。在小脑病变的整个神经解剖学通路中研究了 PrPSc 积累的分布和突触囊泡的免疫反应性。时间进程研究表明，PrPSc 积累显示出从颗粒层扩散到分子层的趋势。囊泡谷氨酸转运蛋白 1 (VGluT1) 的免疫反应性位于小脑颗粒细胞的轴突末端，并且随着 PrPSc 积累的严重程度和颗粒细胞的丢失而降低。分别存在于下橄榄神经元轴突末端和浦肯野细胞 GABA 能突触中的囊泡谷氨酸转运蛋白 2 (VGluT2) 和囊泡 GABA 转运蛋白 (VGAT) 的免疫反应性在这些病变中保存良好。在脑干中，VGluT1 免疫反应性在作为脑桥小脑通路组成部分的脑桥核中选择性降低，尽管其他神经递质免疫反应性保留良好。我们的研究结果表明，PrPSc 积累后 VGluT1 免疫反应性突触的选择性丢失可能有助于 BSE 感染豚鼠小脑病变的发病机制。