Presynaptic impairment in Niemann-Pick C1-deficient neurons: not dependent on presence of glial cells.

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.