Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Cerebellum. 2011 Mar;10(1):88-95. doi: 10.1007/s12311-010-0233-2.
Niemann-Pick type C disease (NPC) is an autosomal recessive lipidosis characterized by progressive neurodegeneration. Although several studies have revealed unusual accumulation of unesterfied cholesterol in astrocytic lysosome of NPC, pathophysiological basis of cerebellar neuronal dysfunction remains unclear. We compared parallel fiber-Purkinje cell synaptic transmission and long-term depression (LTD) in +/+npc (nih) (npc(+/+)) and -/-npc(nih) (npc(-/-)) mice. Our data showed that adenosine A1 receptor agonists decreased parallel fiber excitatory postsynaptic current (EPSC) amplitude and mEPSC frequency while its antagonists increased EPSC amplitude and mEPSC frequency in wild type and mutant mice. Furthermore, parallel fiber LTD was deficient in npc(-/-) mice and supplement of adenosine triphosphate (ATP) rescued the impaired LTD. Taken together, these experiments suggest that synaptic strength and LTD are altered in npc(-/-) mice due to the decrease of ATP/adenosine release and deactivation of A1 receptors in parallel fiber terminals. The enhanced synaptic transmission and the decreased LTD might result in progressive neurotoxicity of Purkinje cells in npc(-/-) mice.
尼曼-匹克 C 型病（NPC）是一种常染色体隐性脂质沉积病，其特征是进行性神经退行性变。尽管有几项研究表明 NPC 星形胶质细胞溶酶体中未酯化胆固醇的异常积累，但小脑神经元功能障碍的病理生理基础仍不清楚。我们比较了 +/+npc（nih）（npc(+/+)）和 -/-npc（nih）（npc(-/-)）小鼠的平行纤维-浦肯野细胞突触传递和长时程抑制（LTD）。我们的数据表明，腺苷 A1 受体激动剂降低了野生型和突变型小鼠平行纤维兴奋性突触后电流（EPSC）幅度和 mEPSC 频率，而其拮抗剂增加了 EPSC 幅度和 mEPSC 频率。此外，npc(-/-) 小鼠的平行纤维 LTD 缺失，三磷酸腺苷（ATP）的补充挽救了受损的 LTD。总之，这些实验表明，由于平行纤维末端 ATP/腺苷释放减少和 A1 受体失活，npc(-/-) 小鼠的突触强度和 LTD 发生改变。增强的突触传递和减少的 LTD 可能导致 npc(-/-) 小鼠浦肯野细胞的进行性神经毒性。
