Oligomeric and fibrillar species of the synaptic protein α-synuclein are established key players in the pathophysiology of Parkinson's disease and other synucleinopathies. Increasing evidence in the literature points to prefibrillar oligomers as the main cytotoxic species driving dysfunction in diverse neurotransmitter systems even at early disease stages. Of note, soluble oligomers have recently been shown to alter synaptic plasticity mechanisms at the glutamatergic cortico-striatal synapse. However, the molecular and morphological detrimental events triggered by soluble α-synuclein aggregates that ultimately lead to excitatory synaptic failure remain mostly elusive.