AbstractNiemann‐Pick disease type C (NPC) is a fatal autosomal recessive cholesterol disorder characterized by severe progressive neurodegeneration. To unveil the mechanism of neurodegeneration, proteomic and morphological approaches were applied to the hippocampus in NPC –/– mouse. Two‐DE was utilized to resolve the hippocampal protein expression profiles of 4‐ and 8‐week‐old NPC +/+ and –/– mice. Differentially expressed protein spots were identified by MALDI‐TOF MS and database searching. At 4 weeks of age, there was no significant difference in protein profiles between NPC +/+ and –/– mice. However, at the age of 8 weeks, NPC +/+ and –/– mice showed marked difference in protein expressions. Among these, glutamate receptor 2 precursor was identified. The immunohistochemical study on neurotransporters showed that glial GABA transporter (GAT‐3) increased in both 4‐ and 8‐week‐old NPC –/– mouse and glutamic acid decarboxylase (GAD‐6) increased in 8‐week‐old NPC –/– mouse. Glial glutamate transporter, excitatory amino acids carrier‐1 (EAAC1), decreased in 8‐week‐old NPC –/– mouse. In conclusion, our data may provide insight into the understanding of the basic mechanism through perturbation of protein networks and neurotransporter systems in a single gene knockout model of NPC disease.