Objective: Nieman-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 gene. At the present, its function is unknown, although several studies have suggested that NPC1 modulates cholesterol transport. Mutations in the NPC1 gene may cause neuronal dysfunction, including dystonia, dementia and seizures, suggesting possible interactions with cellular excitability and network plasticity. This study hence focuses on the analysis of the NPC1 mutation on network plasticity in neuronal circuits involved in cognition, movement coordination and seizure generation in an animal NPC1-knockout model. Methods: Short- and long-term plasticity as well as input-output relationships were investigated in hippocampal, corticostriatal and neocortical slices using field extracellular recordings (stratum radiatum hippocampal CA1 area, dorsomedial striatum, neocortical layer 2/3) and electrical stimulation of respective afferent/associative fibres (Schaffer collateral fibres, cortico-striatal afferents, layer 6 or parallel layer 2). Results: The main findings were: a. Tetanically- induced long-term potentiation in the hippocampus, striatum as well as in layer 2 or 3 of neocortex were not altered in NPC mutant slices as compared to controls. By contrast, theta-burst induced LTP in neocortical slices was significantly reduced in NPC1 deficient preparations. b. Network excitability and short- term hippocampal and corticostriatal plasticity were not different between control and NPC1-/- preparations c. Again by contrast, neocortical network excitability was significantly enhanced in NPC1-deficient tissue, as evidenced by significant increases of input-output relationships. Conclusion: The partial loss of neocortical synaptic plasticity together with the increase of network excitability suggest that NPC1 protein is instrumental in the regulation of excitability of neocortex, possibly saturating it, thereby infringing synaptic plasticity.