Exogenous Alpha-Synuclein Hinders Synaptic Communication In Cultured Cortical Primary Rat Neurons

Amyloid aggregates of the protein alpha-synuclein (alpha S) called Lewy Bodies (LB) and Lewy Neurites (LN) are the pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. We have previously shown that high extracellular alpha S concentrations can be toxic to cells and that neurons take up alpha S. Here we aimed to get more insight into the toxicity mechanism associated with high extracellular alpha S concentrations (50-100 mu M). High extracellular alpha S concentrations resulted in a reduction of the firing rate of the neuronal network by disrupting synaptic transmission, while the neuronal ability to fire action potentials was still intact. Furthermore, many cells developed alpha S deposits larger than 500 nm within five days, but otherwise appeared healthy. Synaptic dysfunction clearly occurred before the establishment of large intracellular deposits and neuronal death, suggesting that an excessive extra cellular alpha S concentration caused synaptic failure and which later possibly contributed to neuronal death.