Abstract
Neuronal inclusions composed of α-synuclein (α-syn) characterize Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. α-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic α-syn causes neuronal defects, we induced endogenous α-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with α-syn fibrils. At seven days after adding fibrils, α-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from α-syn knockout mice, suggesting that the changes in spine morphology result from fibril-induced corruption of endogenously expressed α-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to α-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death.
Highlights
Neuronal inclusions composed of α-synuclein (α-syn) define Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) [5]
We found that formation of α-syn inclusions increased the frequency of presynaptic action potential-independent miniature excitatory postsynaptic currents (EPSCs) (mEPSCs) with increased number of docked presynaptic vesicles, despite a major reduction in dendritic spine density
Inclusions localized to axons at initial time points after their formation which was induced by exposure of the neurons to α-syn fibrils generated from mouse α-syn (2 μg/mL) (Fig. 1b). p-αSyn colocalized with tau, an axonal marker, at 7 days post fibril addition with minimal overlap with MAP2 in dendrites (Additional file 1: Figure S1A)
Summary
Neuronal inclusions composed of α-synuclein (α-syn) define Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) [5]. Identifying if and how synaptic dysfunction occurs in PD and DLB could point to novel therapeutic strategies to prevent or reverse neuronal defects and halt development of dementia. Pathologic staging studies suggest that axonal Lewy neurites form before somal Lewy bodies and presynaptic aggregates of α-syn are highly abundant in DLB [9, 10, 26]. Presynaptic aggregates of α-syn in the cortex of DLB patients correspond to reduced dendritic spines, suggesting they contribute to synapse loss and cognitive dysfunction [26]. Multiple lines of evidence point to a role for α-syn at the presynaptic terminal and that presynaptic and axonal pathologic α-syn aggregates may contribute to neuronal dysfunction, it is unknown if formation of axonal α-syn inclusions impacts neuronal structure and function
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