Aggregated α-synuclein leads to corticostriatal synaptic dysfunction

Abstract

Neuronal inclusions of -synuclein (-syn) are pathological hallmarks of Parkinsons disease (PD) and Dementia with Lewy Bodies (DLB). -Syn pathology accumulates in cortical neurons which project to the striatum. To begin to understand how -syn pathology effects cortico-striatal synapses, pre-formed -syn fibrils (PFF) were injected into the striatum to induce robust -syn aggregation in corticostriatal-projecting neurons. Electrophysiological recordings of striatal spiny projection neurons (SPNs) acute slices found a significant decrease in evoked corticostriatal glutamate release in mice with PFF-induced aggregates compared to monomer injected mice. Expansion microscopy, confocal microscopy and Imaris reconstructions were used to identify vGLUT1 positive presynaptic terminals juxtaposed to Homer-positive postsynaptic densities, termed synaptic foci. Quantitation of synaptic loci density revealed a loss of corticostriatal synapses. Immunoblots of the striatum show reductions in expression of pre-synaptic proteins with selective reduction in AMPA and NMDA receptor subunits in mice with -syn aggregates compared to controls. Paradoxically, a small percentage of remaining VLGUT1+ synaptic loci with small, intrasynaptic -syn aggregates showed enlarged volumes compared to nearby synapses without -syn aggregates. Our combined physiology and high-resolution imaging data point to dysfunction of corticostriatal synapses in mice harboring {square}-synuclein inclusions, which may contribute to impaired basal ganglia circuitry in PD. Highlights- Corticostriatal glutamate drive is impaired in the presence of pathological -syn - -Syn aggregation causes early loss of corticostriatal synapses - Synaptic loci positive for small -syn aggregates show volume increases - Striatal expression of select synaptic proteins are reduced in animals with -syn pathology