Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation
| Autor: | Raquel B. Dias, Lars Lannfelt, Patrícia Guerreiro, Luísa V. Lopes, Joakim Bergström, Francesca Maiolino, Henri G. Franquelim, Miguel A. R. B. Castanho, Ana M. Sebastião, Alexandre Quintas, Thomas Näsström, Maria José Diógenes, Hugo Vicente Miranda, Diogo M. Rombo, Tiago F. Outeiro, Martin Ingelsson, Luís M. A. Oliveira |
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| Přispěvatelé: | Repositório da Universidade de Lisboa |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
a-syn oligomers Patch-Clamp Techniques Parkinson's disease Long-Term Potentiation Synaptic Transmission Alpha-Synuclein Oligomers LTP NMDA-Receptor Activation Biophysics Hippocampus Substantia nigra AMPA receptor Biology Neurotransmission Receptors N-Methyl-D-Aspartate Alpha-synuclein Neuroblastoma 03 medical and health sciences chemistry.chemical_compound Organ Culture Techniques 0302 clinical medicine Cell Line Tumor Animals Humans Insulin Biotinylation Rats Wistar 030304 developmental biology 6-Cyano-7-nitroquinoxaline-2 3-dione Synucleinopathies 0303 health sciences L-Lactate Dehydrogenase General Neuroscience Excitatory Postsynaptic Potentials Extracellular Fluid Valine Long-term potentiation Articles Rats chemistry nervous system Synapses alpha-Synuclein NMDA receptor Excitatory Amino Acid Antagonists Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação instacron:RCAAP |
| Popis: | Copyright © 2012 the authors Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of α-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies. This research is supported by a Marie Curie International Reintegration Grant (Neurofold; T.F.O.), an EMBO Installation Grant, Fundação para a Ciência e Tecnologia (FCT), PTDC/QUI/73430/2006 Grant from FCT (A.Q), PDCT/SAU-NMC/099853/2008 from FCT (L.V.L.), PDCT/SAU-NMC/110838/2009 from FCT (A.M.S.), FCT fellowships SFRH/BD/60386/2009 (D.M.R.) and SFRH/BD/27761/2006 (R.B.D.), FCT fellowship SFRH/BPD/64702/2009 (H.V.M.), and by the University of Rome Sapienza (F.M.). We also thank Alex Kasrayan and Monica Ekberg for the production of recombinant a-syn. |
| Databáze: | OpenAIRE |
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