α-Synuclein aggregates in corticostriatal terminals impair glutamatergic transmission in the absence of neurodegeneration

Abstract

Substantia nigra pars compacta dopamine neuron loss and Lewy pathology, aggregates of α-synuclein, characterize Parkinson’s disease and Dementia with Lewy Bodies. Lewy pathology localizes to cortical neurons, and is found as Lewy neurites in the striatum, but its effects on excitatory synaptic function are just beginning to be understood. Corticostriatal projections regulate motor and cognitive behaviors impaired in these disorders. Here, α-synuclein aggregation was induced in mouse M2 cortex, a vulnerable region in human disease. Early after initiation, aggregates localized to corticostriatal vesicular glutamate transporter 1 (vGLUT1)-positive terminals, with sparing of spiny projection neuron (SPN) soma, and dopamine terminals and neurons. Corticostriatal presynaptic aggregates significantly impaired glutamatergic transmission, without overt cortical neuron loss, and were associated with decreased synaptic density and volume. Thus, formation of presynaptic α-synuclein aggregates impairs corticostriatal function without degeneration of cortical neurons or striatal dopamine terminals, suggesting pathologic α-synuclein is sufficient for synaptic loss. Our findings also point to early synaptic dysfunction as a therapeutic target in Lewy body diseases.