Motor neuropathy-associated mutation impairs Seipin functions in neurotransmission
Autor: | Zhiping P. Pang, Wei-Yi Ong, Stephanie Li-Ying Soh, Julia Xia, Weiping Han, Shunhui Wei |
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Rok vydání: | 2013 |
Předmět: |
Male
Genetic Vectors Mutation Missense Gene Expression Biology Neurotransmission Inhibitory postsynaptic potential Biochemistry Synaptic vesicle Synaptic Transmission Seipin Cellular and Molecular Neuroscience Mice Microscopy Electron Transmission Synaptic augmentation GTP-Binding Protein gamma Subunits medicine Image Processing Computer-Assisted Animals Motor Neuron Disease Cells Cultured Spastic Paraplegia Hereditary Lentivirus Excitatory Postsynaptic Potentials Motor neuron Heterotrimeric GTP-Binding Proteins Immunohistochemistry Mice Inbred C57BL medicine.anatomical_structure Synapses Excitatory postsynaptic potential Synaptophysin biology.protein Female Neuroscience |
Zdroj: | Journal of neurochemistry. 129(2) |
ISSN: | 1471-4159 |
Popis: | Gain-of-toxic-function mutations in Seipin (Asparagine 88 to Serine (N88S) and Serine 90 to Leucine (S90L) mutations, both of which disrupt the N-glycosylation) cause autosomal dominant motor neuron diseases. However, the mechanism of how these missense mutations lead to motor neuropathy is unclear. Here, we analyze the impact of disruption of N-glycosylation of Seipin on synaptic transmission by over-expressing mutant Seipin in cultured cortical neurons via lentiviral infection. Immunostaining shows that over-expressed Seipin is partly colocalized with synaptic vesicle marker synaptophysin. Electrophysiological recordings reveal that the Seipin mutation significantly decreases the frequency, but not the amplitudes of miniature excitatory post-synaptic currents and miniature inhibitory post-synaptic currents. The amplitude of both evoked excitatory post-synaptic currents and inhibitory post-synaptic current is also compromised by mutant Seipin over-expression. The readily releasable pool and vesicular release probability of synaptic vesicles are both altered in neurons over-expressing Seipin-N88S, whereas neither γ-amino butyric acid (GABA) nor α-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) induced whole cell currents are affected. Moreover, electron microscopy analysis reveals decreased number of morphologically docked synaptic vesicles in Seipin-N88S-expressing neurons. These data demonstrate that Seipin-N88S mutation impairs synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse. |
Databáze: | OpenAIRE |
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