Progressive Vulnerability of Cortical Synapses in α-Synucleinopathy

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α-Synuclein aggregates characterize α-synucleinopathies, including Parkinson’s disease and Dementia with Lewy bodies. A majority of people with these disorders experience cognitive decline, and its extent correlates with cortical α-synuclein pathology. Mechanisms by which pathology targets cortical circuits remain to be understood so that the debilitating non-motor impairments can be addressed. Overt neuronal loss is not a major feature of cortical pathology, but a reduction of presynaptic sites has been reported at late stages of PD. We here define excitatory synapses as neuronal loci affected by α-synuclein aggregation, showing that they are progressively lost, and identify temporal and spatial patterns of synaptic vulnerability. Results were obtained in a mouse model using intrastriatal injection of pre-formed α-synuclein fibrils to template the aggregation of endogenous α-synuclein in cortical neurons. Lewy neurite-like aggregates were predominantly observed in axons. Super-resolved imaging showed α-synuclein aggregation within cortical synapses and revealed that synaptic aggregation is most severe proximal to Lewy neurite-like structures and linked to the earliest detectable loss of excitatory synapses. Excitatory synapses also exhibited ultrastructural aberrations, including a redistribution of pre- and post-synaptic protein clusters away from contact sites and reduced synaptic vesicle size. As pathology advanced, VGLUT1-positive intracortical synapses, enriched in α-synuclein, were progressively vulnerable in this striatal seeding model, while VGLUT2-positive long-range synapses with minimal α-synuclein were spared. Inhibitory synapses were not affected. In agreement with a disruptive role of synaptic α-synuclein aggregation, super-resolved mesoscale imaging determined that synaptic but not non-synaptic α-synuclein pathology is correlated with excitatory synapse loss. Physiological recordings confirmed impaired excitatory neurotransmission. Pathology propagation tracked cortical connectivity, with intra-column synapse loss correlated between interconnected layers V and II/III. Contralateral areas receiving projections from pathologic layer V also exhibited synapse loss. These findings reveal synapses as principal cellular loci of α-synuclein pathology and define how molecular and circuit-based mechanisms underlie the cortical progression of synaptic pathology in α-synucleinopathies.

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