title: AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced α-synuclein oligomers.
abstract: Aggregated α-synuclein (α-syn) is a characteristic pathological finding in Parkinson's disease and related disorders, such as dementia with Lewy bodies. Recent evidence suggests that α-syn oligomers represent the principal neurotoxic species; however, the pathophysiological mechanisms are still not well understood. Here, we studied the neurophysiological effects of various biophysically-characterized preparations of α-syn aggregates on excitatory synaptic transmission in autaptic neuronal cultures. Nanomolar concentrations of large α-syn oligomers, generated by incubation with organic solvent and Fe(3+) ions, were found to selectivity enhance evoked α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-receptor, but not NMDA-receptor, mediated synaptic transmission within minutes. Moreover, the analysis of spontaneous AMPA-receptor-mediated miniature synaptic currents revealed an augmented frequency. These results collectively indicate that large α-syn oligomers alter both pre- and post-synaptic mechanisms of AMPA-receptor-mediated synaptic transmission. The augmented excitatory synaptic transmission may directly contribute to nerve cell death in synucleinopathies. Indeed, already low micromolar glutamate concentrations were found to be toxic in primary cultured neurons incubated with large α-syn oligomers. In conclusion, large α-syn oligomers enhance both pre- and post-synaptic AMPA-receptor-mediated synaptic transmission, thereby aggravating intracellular calcium dyshomeostasis and contributing to excitotoxic nerve cell death in synucleinopathies.
authors.affiliation: Center of Neuropathology and Prion Research, Ludwig Maximilians University, Munich, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hüls
authors.forename: Tobias
authors.initials: T
authors.lastname: Högen
authors.forename: Neville
authors.initials: N
authors.lastname: Vassallo
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D055724:Electrophysiological Phenomena; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D051379:Mice; D018613:Microscopy, Confocal; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000494:pharmacology*
chemical_list: D005456:Fluorescent Dyes; D018091:Receptors, AMPA; D011994:Recombinant Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D051844:alpha-Synuclein; D007501:Iron; C022616:thiazolyl blue