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Cortical synaptic vulnerabilities revealed in an α-synuclein aggregation model of Parkinson’s disease
Output Details
Description
Cognitive impairment is a frequent non-motor symptom in Parkinson’s disease (PD) and is strongly associated with cortical Lewy pathology. Synaptic pathology, which has been reported in PD patients, can contribute to impaired cortical function. Yet, the extent of synapse vulnerability in the PD cortex and its spatial relationship to areas exhibiting pathology remains to be defined. We employed high-resolution imaging to analyze synaptic abnormalities in the cortex of mice injected with a-synuclein pre-formed fibrils. Mice were injected in the striatum to cause pathological aggregation of endogenous a-synuclein in cortical neurons projecting to this region. We observe that cortical pathology is linked to the progressive loss of excitatory synapses, followed by a reduction in inhibitory postsynaptic sites. Synapses exhibit a-synuclein aggregates, and synapse loss is most pronounced in areas with high pathology. Gene ontology analysis of synaptic genes whose expression is altered in pathology-bearing neurons supports select changes in synaptic vesicle and postsynaptic proteins and synapse-organizing pathways. In agreement, we observe structural changes in the remaining excitatory synaptic loci, including smaller synaptic vesicles and tighter vesicle clustering. Moreover, synaptic function is compromised, and excitatory but not inhibitory transmission is impaired in early pathological conditions. Our results demonstrate that a-synuclein aggregation in the cortex is linked to molecular and structural synaptic alterations that disrupt connectivity and transmission. This provides insights into the temporal profile and pathological properties of excitatory and inhibitory synaptic vulnerability in the PD cortex.
Identifier (DOI)
10.1101/2024.06.20.599774