Presynaptic impairment in Niemann–Pick C1-deficient neurons: Not dependent on presence of glial cells
Presynaptic impairment in Niemann–Pick C1-deficient neurons: Not dependent on presence of glial cells
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DOI：
10.1016/j.neulet.2011.03.097
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发表时间：
2011-05
影响因子：
2.5
通讯作者：
Shujun Xu;Xiaowei Chen;Xiaofei Wei;Guilan Liu;Qinwen Wang
中科院分区：
文献类型：
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作者：
Shujun Xu;Xiaowei Chen;Xiaofei Wei;Guilan Liu;Qinwen Wang
C型尼曼-皮克病(NPC)是一种进行性神经退行性疾病，其特征是游离胆固醇在晚期内切/溶酶体内积聚。这种疾病的病理基础还知之甚少。在我们之前的研究中，我们已经证明了这种疾病的突触功能受损。在目前的研究中，电生理和荧光染料的研究被用来确定突触缺陷是由突触前还是突触后的贡献引起的。此外，我们想要确定这些缺陷是由神经元中NPC1缺乏的直接作用还是神经胶质细胞中NPC1缺乏的间接作用引起的。NPC1−/−神经元的微小兴奋性突触后电流(MEPSC)和微小抑制性突触后电流(MIPSCs)的平均事件间期均显著大于野生型神经元，但其波幅和受体动力学与野生型对照无明显差异。NPC1−/−神经元突触囊泡的胞吐速度也较慢。无论有无神经胶质细胞，NPC1−/−神经元的平均染色时间常数均大于野生型对照。以上结果表明，NPC1−/−神经元普遍存在突触前功能损害，这种损害不依赖于神经胶质细胞。因此，鼻咽癌疾病的神经病理学特征可能更可能是神经元突触前功能障碍的结果，而不是胶质细胞的间接缺陷。
Niemann–Pick disease type C (NPC) is a progressive neurodegenerative disorder characterized by accumulation of free cholesterol in late endosomes/lysosomes. The pathological basis for the disease has been poorly understood yet. In our previous study, we have demonstrated that synaptic function is impaired in this disease. In the current study, electrophysiological and fluorescent dyes studies were used to determine whether the synaptic defects result from presynaptic or postsynaptic contributions. Furthermore, we would like to ascertain whether such defects are caused by direct effect of NPC1 deficiency in neurons or indirect effect of NPC1 deficiency in glial cells. Both mean inter-event interval of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) were significantly larger in NPC1−/−neurons than those in the wild-type neurons, while the amplitudes and the receptor kinetics were not different compared with those in wild-type controls. Synaptic vesicle exocytosis was also slower in the NPC1−/−neurons. The mean time constant of destaining was larger in NPC1−/−neurons than in wild-type controls both in the presence and absence of glial cells. All these results indicated a general presynaptic functional impairment in the NPC1−/−neurons and such defects were not dependent of glial cells. Therefore, neuropathology characteristics of NPC diseases may be a more possible consequence of neuronal presynaptic dysfunction than indirect defects in glial cells.