AMPA-receptor-mediated excitatory synaptic transmission is enhanced by iron-induced α-synuclein oligomers

P>Aggregated alpha-synuclein (alpha-syn) is a characteristic pathological finding in Parkinson's disease and related disorders, such as dementia with Lewy bodies. Recent evidence suggests that alpha-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 alpha-syn aggregates on excitatory synaptic transmission in autaptic neuronal cultures. Nanomolar concentrations of large alpha-syn oligomers, generated by incubation with organic solvent and Fe3+ ions, were found to selectivity enhance evoked alpha-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 alpha-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 alpha-syn oligomers. In conclusion, large alpha-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.