Defects of synaptic vesicle turnover at excitatory and inhibitory synapses in Niemann-Pick C1-deficient neurons

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 is poorly understood. In the present study, electrophysiological and fluorescent dye studies were applied to examine neuron-specific functions of Niemann-Pick disease type C1 (NPC1) and to determine whether excitatory and inhibitory synapses are differentially impaired by NPC1 deficiency. Densities of spines and postsynaptic receptor clusters were not affected by NPC1 deficiency over the period examined. However, drastic defects on exocytosis were found both in glutamatergic and GABAergic synapses. The defects were caused in part by a delay in the time required for replacement of excytosed vesicles with new fusion-competent ones. Moreover, we found that the delay of synaptic vesicle turnover was longer in inhibitory synapses (>3 s) than in excitatory synapses (<0.2 s). These defects may be early indicators, and could provide a potential explanation for key features of the disease, such as dystonia and seizures.