Abstract
Niemann-Pick Disease Type C1 (NPC1) is a rare hereditary neurodegenerative disease belonging to the family of lysosomal storage disorders. NPC1-patients suffer from, amongst other symptoms, ataxia, based on the dysfunction and loss of cerebellar Purkinje cells. Alterations in synaptic transmission are believed to contribute to a pathological mechanism leading to the progressive loss of Purkinje cells observed in NPC1-deficient mice. With regard to inhibitory synaptic transmission, alterations of GABAergic synapses are described but functional data are missing. For this reason, we have examined here the inhibitory GABAergic synaptic transmission of Purkinje cells of NPC1-deficient mice (NPC1−/−). Patch clamp recordings of inhibitory post-synaptic currents (IPSCs) of Purkinje cells revealed an increased frequency of GABAergic IPSCs in NPC1−/− mice. In addition, Purkinje cells of NPC1−/− mice were less amenable for modulation of synaptic transmission via the activation of excitatory NMDA-receptors (NMDA-Rs). Western blot testing disclosed a reduced protein level of phosphorylated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) subunit GluA2 in the cerebella of NPC1−/− mice, indicating a disturbance in the internalization of GluA2-containing AMPA-Rs. Since this is triggered by the activation of NMDA-Rs, we conclude that a disturbance in the synaptic turnover of AMPA-Rs underlies the defective inhibitory GABAergic synaptic transmission. While these alterations precede obvious signs of neurodegeneration of Purkinje cells, we propose a contribution of synaptic malfunction to the initiation of the loss of Purkinje cells in NPC1. Thus, a prevention of the disturbance of synaptic transmission in early stages of the disease might display a target with which to avert progressive neurodegeneration in NPC1.
Highlights
Niemann Pick Type C1 (NPC1) is a recessive inherited neurovisceral lipidosis with an estimated incidence of 1:120,000 [1]
Since we have recently reported a disturbed internalization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) containing the GluA2 subunit [10,11] and that the GABAergic input to the Purkinje cells (PCs) can be tuned by N-methyl-D-aspartate receptors (NMDA-Rs) and subsequently by AMPA-Rs [12], we examined in addition the modulation of the synaptic input to PCs by activating NMDA-Rs and the expression of the GluA2 subunit of AMPA-Rs
Progressive loss of Purkinje cells is a hallmark of NPC1, wherein different NPC1 mice models show progressive cell loss propagating from the anterior to posterior lobes [3,4,5]
Summary
Niemann Pick Type C1 (NPC1) is a recessive inherited neurovisceral lipidosis with an estimated incidence of 1:120,000 [1]. Studies in NPC1 mice models have revealed progressive cell loss propagating from the anterior to the posterior lobes, whereas no prominent loss of PCs has been observed in lobe 10 [3,4,5]. The pathological mechanism underlying the loss of PCs is not yet well understood and only a few studies describe functional alterations in PCs of NPC1−/− mice at an age without any obvious signs of cell loss or motoric dysfunction. With regard to inhibitory synaptic transmission mediated by gamma-aminobutyric acid receptor (GABAA-Rs), an altered number of GABAergic synapses has been described in NPC1-deficient mice, but functional data are not available [9]. We examined inhibitory postsynaptic currents (IPSCs), mediated by GABAA-Rs, to elucidate alterations of the synaptic transmission between cerebellar interneurons and Purkinje cells. Since we have recently reported a disturbed internalization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-Rs) containing the GluA2 subunit [10,11] and that the GABAergic input to the PCs can be tuned by N-methyl-D-aspartate receptors (NMDA-Rs) and subsequently by AMPA-Rs [12], we examined in addition the modulation of the synaptic input to PCs by activating NMDA-Rs and the expression of the GluA2 subunit of AMPA-Rs
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