Abnormal Alpha-Synuclein Aggregates Cause Synaptic- and Microcircuit-specific Deficits in the Retinal Rod Pathway

Abstract

Alpha-synuclein (α-Syn) is a key determinator of Parkinson's disease (PD) pathology, but synapse and microcircuit pathologies in the retina underlying visual dysfunction are poorly understood. Using the old transgenic M83 PD model (16-18 monthes) coupled with histochemical and ultra-structural analyses and ophthalmologic measurements, we revealed that abnormal α-Syn aggregation in the outer plexiform layer (OPL) was associated with degeneration in the CtBP2⁺ ribbon synapses of photoreceptor terminals and PKCα⁺ rod bipolar cells terminals while α-Syn aggregates in the inner retina correlated with the reduction and degeneration of tyrosine hydroxylase (TH)- and parvalbumin (PV)-positive amacrine cells. Phosphorylated Ser129 α-synuclein expression was strikingly restricted in the OPL with the most severe degenerations in the entire retina, including mitochondrial degeneration and loss of ribbon synapses in 16-18-month-old mice. These synapse- and microcircuit-specific deficits of the rod pathway at the CtBP2⁺ rod terminals and PKCα⁺ rod bipolar and amacrine cells were associated with attenuated a- and b-wave amplitudes and oscillatory potentials on the electroretinogram. They were also associated with the impairment of visual functions, including reduced contrast sensitivity and impairment of the middle range of spatial frequencies. Collectively, these findings demonstrate that α-Syn aggregates cause the synapse- and microcircuit-specific deficits of the rod pathway and the most severe damage to the OPL, providing the retinal synaptic and microcircuit basis for visual dysfunctions in PD.