Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation.
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.
Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Ed. Egas Moniz, 1649-028 Lisboa, Portugal.
Maria José
MJ
Diógenes
Raquel B
RB
Dias
Diogo M
DM
Rombo
Hugo
H
Vicente Miranda
Francesca
F
Maiolino
Patrícia
P
Guerreiro
Thomas
T
Näsström
Henri G
HG
Franquelim
Luís M A
LM
Oliveira
Miguel A R B
MA
Castanho
Lars
L
Lannfelt
Joakim
J
Bergström
Martin
M
Ingelsson
Alexandre
A
Quintas
Ana M
AM
Sebastião
Luísa V
LV
Lopes
Tiago Fleming
TF
Outeiro
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001703:Biophysics; D019921:Biotinylation; D045744:Cell Line, Tumor; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D045604:Extracellular Fluid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009447:Neuroblastoma / Q000473:pathology; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D007328:Insulin; D016194:Receptors, N-Methyl-D-Aspartate; D051844:alpha-Synuclein; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D007770:L-Lactate Dehydrogenase; D014633:Valine