{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T21:04:21Z","timestamp":1781557461118,"version":"3.54.5"},"reference-count":61,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2016,3,24]],"date-time":"2016-03-24T00:00:00Z","timestamp":1458777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,5,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The presynaptic protein \u03b1\u2010synuclein forms aggregates during Parkinson's disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Accumulating evidence suggests that the small soluble oligomers of \u03b1\u2010synuclein are more toxic than the larger aggregates appearing later in the disease.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The link between oligomer toxicity and structure still remains unclear.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In the present study, we have produced two structurally\u2010defined oligomers that have a similar morphology but differ in secondary structure.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These oligomers were introduced into neocortical pyramidal cells during whole\u2010cell recording and, using a combination of experimentation and modelling, electrophysiological parameters were extracted.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Both oligomeric species had similar effects on neuronal properties reducing input resistance, time constant and increasing capacitance. The net effect was a marked reduction in neuronal excitability that could impact on network activity.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The presynaptic protein \u03b1\u2010synuclein (\u03b1Syn) 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, \u03b1Syn forms soluble annular oligomers that show greater toxicity than much larger fibrils. These oligomers produce toxicity via a number of possible mechanisms, including the production of pore\u2010forming complexes that permeabilize membranes. In the present study, two well\u2010defined species of soluble \u03b1Syn oligomers were produced by different protocols: by polymerization of monomer and by sonication of fibrils. The two oligomeric species produced were morphologically similar, with both having an annular structure and consisting of approximately the same number of monomer subunits, although they differed in their secondary structure. Oligomeric and monomeric \u03b1Syn were injected directly into the soma of pyramidal neurons in mouse neocortical brain slices during whole\u2010cell 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: (i) a significant reduction in input resistance and the membrane time constant and (ii) an increase in the current required to trigger an action potential with 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 \u03b1Syn had no effect on neuronal parameters, even at high concentrations. The oligomer\u2010induced fall in neuronal excitability has the potential to impact both network activity and cognitive processing.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp271968","type":"journal-article","created":{"date-parts":[[2016,2,26]],"date-time":"2016-02-26T08:50:38Z","timestamp":1456476638000},"page":"2751-2772","source":"Crossref","is-referenced-by-count":49,"title":["Intracellular soluble \u03b1\u2010synuclein oligomers reduce pyramidal cell excitability"],"prefix":"10.1113","volume":"594","author":[{"given":"Timothy J.","family":"Kaufmann","sequence":"first","affiliation":[{"name":"School of Life Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Warwick Systems Biology Centre University of Warwick  Coventry UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus J. 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