Early α-synuclein aggregation decreases corticostriatal glutamate drive and synapse density

Area of Science:

• Neuroscience
• Pathology
• Synaptic Plasticity

Background:

• Neuronal alpha-synuclein (α-syn) inclusions are key markers of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB).
• α-Syn pathology affects cortical neurons projecting to the striatum, impacting basal ganglia circuitry.

Purpose of the Study:

• To investigate the early effects of α-syn pathology on cortico-striatal synapses before significant dopamine neuron loss.
• To understand how induced α-syn aggregation influences synaptic function and structure in the striatum.

Main Methods:

• Injection of pre-formed α-syn fibrils (PFF) into the striatum to induce endogenous α-syn aggregation in corticostriatal neurons.
• Electrophysiological recordings of striatal spiny projection neurons (SPNs) to measure glutamate release.
• Expansion microscopy, confocal microscopy, and Imaris reconstructions to quantify synaptic loci (VGLUT1+/Homer1+).
• Immunoblotting to assess pre-synaptic protein expression (VGLUT1, VAMP2, Snap25).

Main Results:

• A significant decrease in evoked corticostriatal glutamate release and synaptic release sites was observed in mice with PFF-induced α-syn aggregates.
• Quantitation revealed an early loss of corticostriatal synapses (synaptic loci density).
• Reductions in pre-synaptic proteins VGLUT1, VAMP2, and Snap25 were found in the striatum of mice with α-syn aggregates.
• A subset of synapses with α-syn aggregates showed enlarged volumes compared to unaffected synapses.

Conclusions:

• The study demonstrates an early loss of cortico-striatal synapses in mice with α-synuclein inclusions.
• This synaptic loss may contribute to the impaired basal ganglia circuitry observed in PD and DLB.
• These findings highlight synaptic dysfunction as an early event in α-synucleinopathies.