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Title: Investigating the effects of Zeta Inhibitory Peptide on AMPAR trafficking
Author: Barker, Ellen
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2012
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In recent years, several studies have suggested a role for PKMs, an atypical isoform of PKC, in memory consolidation and long-term potentiation (LTP). Some evidence in support of this theory has come to light, in the form of electrophysiological and behavioural studies, using inhibition, knockdown, perfusion of the molecule itself and overexpression. Exogenously applying the PKM~ to systems leads to potentiation. Conversely, application of Zeta Inhibitory Peptide (ZIP), a peptide sequence purported to inhibit PKMs, consistently reverses LTP and in most cases, erases memories. To date, however, studies on PKMs have focused on functional aspects of PKMs activity (i.e. behaviour and synaptic function) while the molecular events underlying these processes are poorly understood and there are currently few published studies closely examining such details. The experiments performed for this thesis attempt to better understand the molecular effects of ZIP in AMPAR trafficking, and result in some novel findings on the subunitspecific effects, the mechanisms involved, as well as some data showing effects of different concentration of inhibitor. Experiments performed for this project showed that ZIP causes an increase in internalisation of GluAl and GluA2 subunits, and a decrease in surface GluA2, but not GluAl. Previously it had been reported that ZIP leads to a decrease in synaptic function and loss of memory, and this effect can be blocked by preventing GluA2 internalisation. These data are therefore consistent with published studies and also show a new effect regarding the trafficking of the GluAl subunit. It was also shown that PICKl interaction with GluA2, as well as actin depolymerisation are required for the increase in internalization (Rocca et al., 2008) and that PICKl interaction with GluA2 may be increased in the presence of ZIP. These new data support the theory NSF and PICKl are involved in the trafficking activity of PKMs on GluA2 (Yao et al., 2008), and that the loss of synaptic function observed in the presence of ZIP requires PICKl (Yao et al., 2008).
Supervisor: Henley, Jeremy ; Graham Collingridge ; Banting, George Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available