Van Rensburg, Ruan (2007) Upregtilation of neuronal α7 nicotinic acetylcholine receptors and preconditioning. Doctoral thesis, Durham University.
The upregulation of alpha 7 nicotinic acetylcholine receptors (α7 nAChRs) are putatively reported to play a role in in vivo cortical spreading depression-elicited neuroprotection. In this study, a reliable in vitro spreading depression model was created for studying this phenomenon. In contradiction to previous studies, it was, however, shown that functional α 7 nAChRs are down-regulated upon chronic depolarisation with KCl, although the activity of this receptor subtype remained essential for the preconditioning mechanism. Evidence was provided for a differential mechanism underlying protection against NMDA-mediated and hypotonic-shock induced cell loss. Non-pharmacological upregulation of the α 7 nAChRs in pure neuronal cortical cultures by means of a recombinant adenovirus led to the increased cell death subsequent to an excitotoxic glutamate insult. In addition, in order to study the relationship between α7 nAChRs and its function-dependent regulator Ric3, a novel anti-Ric3 antibody and a recombinant adenovirus expressing the ric3 gene were created. Ric3 was found to be expressed in many important brain structures, including hippocampus, perhinal cortex, thalamic and hypothalamic paraventricular nucleus, structures implicated in both cognitive and emotional behaviours. Interestingly, Ric3 was also expressed in the choroid plexus, a non-neuronal cell type not known to α 7 nAChRs, indicating additional roles for this protein. The recombinant constructs expressing ric3, α 7 nAChRs and dual ric3/ α 7 nAChRs were all validated in vitro.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||08 Sep 2011 18:32|