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dc.contributor.advisorAshton, John C
dc.contributor.advisorMockett, Bruce
dc.contributor.advisorSmith, Paul
dc.contributor.authorMaggo, Simran Deep Singh
dc.date.available2013-11-18T20:54:42Z
dc.date.copyright2013
dc.identifier.citationMaggo, S. D. S. (2013). Statin-induced deficits in memory and learning: A behavioural and electrophysiological investigation (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/4452en
dc.identifier.urihttp://hdl.handle.net/10523/4452
dc.description.abstractStatins play a crucial role in reducing the risk of death from cardiovascular disease in millions of people worldwide. Recently, data show people taking statins are at increased risk of a number of psychiatric adverse events such as amnesia, anxiety and even aggression. However, there are conflicting epidemiological data and a scarcity of direct experimental evidence that statins can alter neural functioning. This thesis aimed to investigate the effect of statin treatment on memory in an animal model of spatial memory and learning; the Morris Water maze (MWM) using guinea pigs. The behavioural results demonstrate that statins, independent of their musculoskeletal or liver adverse effects, significantly induced deficits in specific aspects of the MWM. Statins at a clinically equivalent dose of 20mg/d did not affect reference memory directly by affecting latency or distance to platform, but resulted in increased thigmotactic activity. Further behavioural investigations using a higher dose and modified protocol showed once again that statins did not affect spatial reference memory; however, statin treatment for six weeks induced deficits in spatial working memory (short-term memory). Mechanisms of memory have been hypothesised to result from changes in synaptic plasticity in the hippocampus. Extracellular field recordings of synaptic transmission in area CA1 of hippocampal slices were conducted to assess the effects of statin application on LTP. Statins significantly reduced the amount of LTP expressed in a dose-dependent manner. Further investigations with methyl-beta-cyclodextrin (MBCD), a compound that sequesters cholesterol from lipid membranes, demonstrated that statins act independently of cholesterol reduction to decrease the expression of LTP. Furthermore, statins did not affect paired pulse facilitation, but induction of LTP reduced the paired pulse ratio (PPR) in statin-treated slices. These results therefore suggest that statins may induce paired pulse depression after the induction of LTP. To assess these findings further and provide clinical consensus, the effect of six weeks of chronic statin administration on LTP was investigated. Hippocampal slices from statin-treated animals showed reduced expression of LTP compared with vehicle treated animals; however, this was not statistically significant. It is possible that behavioural training prior to electrophysiological assessment could have obscured from detection of any deficits in LTP following chronic statin treatment. To further investigate the molecular mechanisms of statin-induced deficits, western blot analysis of GluN1 and GluA1, specific subunits of glutamatergic receptors known to be critically involved in memory and learning were assessed. Statins induced a 1.5 fold increase in GluA1 but did not affect the expression of GluN1. In conclusion, the results of this thesis demonstrate that statins administered to healthy guinea pigs, at clinically relevant doses, can induce specific behavioural deficits in spatial memory. Furthermore, statins attenuated hippocampal LTP (in vitro), independently of their cholesterol-lowering properties. This thesis has taken the first step in providing evidence to suggest how statins may induce deficits in memory and learning, and in the process has led to new understandings of the role of statins in hippocampal synaptic plasticity, memory and learning.
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectStatins
dc.subjectmemory
dc.subjectamnesia
dc.subjectpharmacovigilance
dc.subjectLTP
dc.subjectelectrophysiology
dc.subjecthippocampus
dc.subjectcholesterol
dc.titleStatin-induced deficits in memory and learning: A behavioural and electrophysiological investigation
dc.typeThesis
dc.date.updated2013-11-18T08:02:36Z
dc.language.rfc3066en
thesis.degree.disciplinePharmacology & Toxicology
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.interloanyes
otago.openaccessAbstract Only
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