Backtracking α-synuclein pathology: social deficits precede motor symptoms in Parkinson’s disease

In Parkinson's disease (PD), degeneration of dopaminergic neurons in the substantia nigra pars compacta and accumulation of alpha-synuclein (α-syn) aggregates are linked to motor impairments. However, up to 80% of PD patients also experience cognitive and psychiatric issues. The effects of α-syn aggregates on limbic structures involved in social behavior are less studied. Here, we hypothesize that early synaptic changes in the mesolimbic dopaminergic system occur before motor symptoms, affecting social cognition (SC). Four weeks after intrastriatal injections of human-α-syn pre-formed fibrils, at a pre-motor stage, dorsolateral striatum plasticity remains intact, while long-term potentiation in the Nucleus Accumbens (NAc)-Core is lost, correlating with deficits in SC and spatial memory. Reduced dopaminergic and glutamatergic inputs and decreased dendritic spine density were also observed. Sub-chronic L-Dopa treatment reversed these changes. Our data suggest that SC is affected early in this synucleinopathy, with synaptic alterations in the NAc-Core playing a key role.