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Niemann-Pick disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease. NPC1-patients suffer, amongst others, from ataxia, based on a loss of cerebellar Purkinje cells (PCs). Impaired expression/function of excitatory amino acid transporters (EAATs) are suspected of contributing to PC-degeneration in hereditary spinocerebellar ataxias (SCAs). Thus, we studied EAAT-expression and its impact to PC-activity in NPC1 −/– mice. Western blot revealed reduced EAAT1, EAAT2, EAAT4, and βIII-spectrin levels in NPC1 −/– mice. EAATs play a crucial role in synaptic transmission, thus we were interested in the impact of the reduced EAAT-expression on the function of PCs. Patch-clamp recordings of PCs showed no differences in the firing patterns of NPC1 +/+ and NPC1 −/– mice using a low internal chloride concentration. Because EAAT4 also comprises a chloride permeable ion pore, we perturbed the chloride homeostasis using a high internal chloride concentration. We observed differences in the firing patterns of NPC1 +/+ and NPC1 −/– mice, suggesting an impact of the altered EAAT4-expression. Additionally, the EAAT-antagonist DL-TBOA acts differently in NPC1 +/+ and NPC1 −/– mice. Our data support the line of evidence that an altered EAAT-expression/function is involved in neurodegeneration of PCs observed in SCAs. Thus, we suggest that similar pathogenic mechanisms contribute the loss of PCs in NPC1.

Impact of Reduced Cerebellar EAAT Expression on Purkinje Cell Firing Pattern of NPC1-deficient Mice