Parkinson’s disease (PD) is one of the most prevalent movement disorders in the world. A clinical hallmark of PD is the appearance of proteinaceous Lewy Bodies throughout the brain that are predominantly formed from aggregation of the presynaptic protein alpha-Synuclein (αSyn). Increasing evidence, however, suggests that the soluble annular αSyn oligomers, formed during early stages of aggregation, are more toxic and pathologically relevant than the larger fibrils which form at later stages of aggregation. The underlying mechanism(s) through which αSyn oligomers exert their toxicity is still largely unknown. This thesis investigates how the toxic nature of αSyn oligomers may affect the electrophysiological properties of neurons. A population of soluble oligomers, termed mOligomers, were isolated from the early stages of in vitro aggregation. In addition, a separate oligomeric species was recovered from the fragmentation of large fibrils; termed fOligomers. Structural characterisation of these two species revealed them to be similar in size and ring-like in shape but showed subtle differences in their secondary structure. Purified, oligomeric αSyn was injected directly into the somata of thick-tufted layer 5 pyramidal neurons in mouse neocortical brain slices during whole-cell patch clamp recording and compared to the effects of equivalent concentrations of αSyn monomer. Using a combined experimental and modelling approach, a wide range of neuronal parameters were extracted and demonstrated oligomer-specific changes in neuronal electrophysiology that were time dependent. Perfusion with αSyn oligomers markedly reduced input resistance, enhanced the current required to trigger an action potential and reduced the firing rate illustrating a reduction in excitability that has the potential to impact both neural circuitry and cognitive output.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:682954 |
| Date | January 2015 |
| Creators | Kaufmann, Timothy J. |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/77758/ |
Page generated in 0.0021 seconds