Intracellular soluble alpha Synuclein oligomers reduce pyramidal cell excitability

Abstract

The presynaptic protein alpha-Synuclein (αSyn) aggregates during Parkinson's disease (PD) to form large proteinaceous amyloid plaques, the spread of which throughout the brain clinically defines the severity of the disease. During early stages of aggregation, αSyn forms soluble annular oligomers that show greater toxicity than much larger fibrils. These oligomers produce toxicity through a number of possible mechanisms including the production of pore-forming complexes that permeabilise membranes. In this study, two well-defined species of soluble αSyn oligomers were produced by different protocols: by polymerisation of monomer and by sonication of fibrils. The two oligomeric species produced were morphologically similar, both having an annular structure and consisting of approximately the same number of monomer subunits, but they differed in their secondary structure. Oligomeric and monomeric αSyn were injected directly into the soma of pyramidal neurons in mouse neocortical brain slices during whole cell patch clamp recording. Using a combined experimental and modelling approach, neuronal parameters were extracted to measure, for the first time in the neocortex, specific changes in neuronal electrophysiology. Both species of oligomer had similar effects: significantly reducing input resistance, the membrane time constant, increasing the current required to trigger an action potential and a resultant reduction in the firing rate. Differences in oligomer secondary structure appeared to produce only subtle differences in the activity of the oligomers. Monomeric αSyn had no effect on neuronal parameters even at high concentrations. The oligomer-induced fall in neuronal excitability has the potential to impact both network activity and cognitive processing.

This article is protected by copyright. All rights reserved

from Physiology via xlomafota13 on Inoreader http://ift.tt/1OwcIvZ
via IFTTT