Glutamatergic neurotransmission in a mouse model of Niemann-Pick Type C Disease.

Niemann–Pick Type C Disease (NPCD) is a progressive neurodegenerative disorder characterized by accumulation of free cholesterol, sphingomyelin, glycosphingolipids (GSLs) and sphingosine in lysosomes, mainly due to a mutation in the NPC1 gene. One of the main symptoms in NPCD patients is hyperexcitability leading to epileptic activity, however, the pathophysiological basis of this neural disorder is not yet well understood. Here we studied the excitatory neurotransmission in the hippocampus of BALB/c NPC1NIH (NPC1−/−) mice, a well-described animal model of the disease. We report that hippocampal field potential population spike (fPS), as well as paired pulse ratio, is enhanced in NPC1−/− with respect to Wild Type (WT). To evaluate the contribution of glutamate receptor activity in the enhanced fPS observed in mutant mice, we recorded slices treated with glutamate receptor agonists alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and Kainate (KA). We found that a prolonged application of KA and AMPA in NPC1−/− mice do not induce the dramatic decrease of synaptic transmission observed in WT hippocampal slices suggesting a functional impairment of presynaptic KA receptors and an imbalance of AMPA receptor exo/endocytosis. In line with electrophysiological data, we also found notable differences in calcium influx during KA and AMPA bath application in NPC1−/− hippocampal culture as compared with WT. Nevertheless in synaptosomal membranes, Western Blot analysis didn't reveal any modification in protein expression levels of KA and AMPA receptor subunits. All together these data indicate that in mutant mice the hyperexcitability, that is at the basis of the insurgence of seizures, might be due to the enhanced glutamatergic neurotransmission caused by an altered KA and AMPA receptor functioning.