1-Methyl-4-phenylpyridinium induces synaptic dysfunction through a pathway involving caspase and PKCdelta enzymatic activities.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration has been used, in various mammalian species, as an experimental model of Parkinson's disease. The pathogenesis for such pharmacologically induced Parkinson's disease involves 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. This metabolite produces rapid degeneration of nigrostriatal dopaminergic neurons, which causes the parkinsonian syndrome. In this work, we show that injection of MPP+ into the presynaptic terminal of the squid giant synapse blocks synaptic transmission without affecting the presynaptic action potential or the presynaptic calcium currents. These effects of MPP+ were mimicked by the injection of an active form of caspase-3 and prevented by inhibitors of caspase-3 and protein kinase C delta. Ultrastructurally, MPP+-injected synapses showed a dramatic reduction in the number of neurotransmitter vesicles at the presynaptic active zone, as compared with control synapses. Otherwise, normal docking and clathrin-coated vesicles were observed, albeit at much reduced numbers. These results indicate that MPP+ acutely reduces presynaptic vesicular availability, not release, and that MPP+-induced pathogenesis results from presynaptic dysfunction that leads, secondarily, to dying-back neuropathy in affected neurons.
Serulle
Yafell
Y
Program in Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA.
Morfini
Gerardo
G
Pigino
Gustavo
G
Moreira
Jorge E
JE
Sugimori
Mutsuyuki
M
Brady
Scott T
ST
Llinás
Rodolfo R
RR
D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D023902:Chromosome Pairing / Q000187:drug effects*; D049832:Decapodiformes; D004195:Disease Models, Animal; D009474:Neurons / Q000473:pathology; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000187:drug effects
D051745:Protein Kinase C-delta; D053148:Caspase 3; D015655:1-Methyl-4-phenylpyridinium