PT  - JOURNAL ARTICLE
AU  - Maria José Diógenes
AU  - Raquel B. Dias
AU  - Diogo M. Rombo
AU  - Hugo Vicente Miranda
AU  - Francesca Maiolino
AU  - Patrícia Guerreiro
AU  - Thomas Näsström
AU  - Henri G. Franquelim
AU  - Luís M.A. Oliveira
AU  - Miguel A.R.B. Castanho
AU  - Lars Lannfelt
AU  - Joakim Bergström
AU  - Martin Ingelsson
AU  - Alexandre Quintas
AU  - Ana M. Sebastião
AU  - Luísa V. Lopes
AU  - Tiago Fleming Outeiro
TI  - Extracellular Alpha-Synuclein Oligomers Modulate Synaptic Transmission and Impair LTP Via NMDA-Receptor Activation
AID  - 10.1523/JNEUROSCI.0234-12.2012
DP  - 2012 Aug 22
TA  - The Journal of Neuroscience
PG  - 11750--11762
VI  - 32
IP  - 34
4099  - http://www.jneurosci.org/content/32/34/11750.short
4100  - http://www.jneurosci.org/content/32/34/11750.full
SO  - J. Neurosci.2012 Aug 22; 32
AB  - 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.