Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson’s disease

Abstract

Cognitive impairment is a frequent non-motor symptom in Parkinson’s disease, and cortical Lewy pathology is strongly associated with cognitive decline. Synaptic pathology has been observed in the PD cortex, but the extent of synaptic vulnerabilities and their temporal and spatial relationship to pathology remains unclear. We employed high-resolution imaging to analyze synaptic abnormalities in layer 5 of the secondary motor cortex. We used striatal injections of α-synuclein pre-formed fibrils as a model to cause the progressive pathological aggregation of endogenous α-synuclein. We find that cortical α-synuclein pathology results in the progressive loss of excitatory synapses, followed by a reduction in inhibitory postsynaptic sites. Synapse loss is most pronounced in areas with high pathology. Additionally, we observed ultrastructural changes in the remaining excitatory synaptic loci, including smaller synaptic vesicles. Consistent with these results, gene ontology analysis of synaptic genes exhibiting altered expression in pathological neurons supported pre- and post-synaptic changes, including in synapse organizing pathways. Our results demonstrate that α-synuclein aggregation in the cortex is linked to molecular and structural alterations that disrupt synaptic connectivity and provide insights into the progressive PD-relevant vulnerability of cortical synapses.