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α-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons.

Authors :
Froula JM
Henderson BW
Gonzalez JC
Vaden JH
Mclean JW
Wu Y
Banumurthy G
Overstreet-Wadiche L
Herskowitz JH
Volpicelli-Daley LA
Source :
Acta neuropathologica communications [Acta Neuropathol Commun] 2018 May 01; Vol. 6 (1), pp. 35. Date of Electronic Publication: 2018 May 01.
Publication Year :
2018

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 Ca <superscript>2+</superscript> 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.

Details

Language :
English
ISSN :
2051-5960
Volume :
6
Issue :
1
Database :
MEDLINE
Journal :
Acta neuropathologica communications
Publication Type :
Academic Journal
Accession number :
29716652
Full Text :
https://doi.org/10.1186/s40478-018-0537-x