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dc.contributor.advisorWood, Emmaen
dc.contributor.advisorKind, Peteren
dc.contributor.advisorTill, Sallyen
dc.contributor.authorAsiminas, Antoniosen
dc.date.accessioned2017-10-05T12:54:16Z
dc.date.available2017-10-05T12:54:16Z
dc.date.issued2017-07-07
dc.identifier.urihttp://hdl.handle.net/1842/23634
dc.description.abstractFragile X syndrome (FXS) is the leading single gene cause of intellectual disability and Autism Spectrum Disorder (ASD). It is caused by epigenetic silencing of the fragile X mental retardation gene (FMR1), causing a loss of Fragile-X Mental Retardation Protein (FMRP). Over the last 2 decades, much has been learned about the pathophysiology related to the loss of FMRP from mouse models of FXS. The recent generation of a rat model of FXS opens the door to: validate phenotypes across mammalian species, address cognitive dysfunction using paradigms that are more difficult to address in mice and explore candidate therapeutics more accurately. This thesis explored the validity of a new rat model for FXS (Fmr1 KO rat). I showed that Fmr1 KO rats exhibit normal spatial navigation memory, social interactions and anxiety levels. On the contrary, when subjects were tested in a battery of spontaneous exploration tasks: object recognition (OR), object-context (OC), object-place (OP), and object-place-context (OPC) recognition, which assess associative memory, Fmr1 KO rats showed a severe deficit in remembering the most complex (episodic-like) associations. Following these results, I sought to explore the development of associative memory from postnatal day 25 (P25) to adulthood (P71). Subjects were tested in the four spontaneous exploration tasks, previously mentioned, 8 times between P25 and P71 to assess the development of their ability to discriminate novel from familiar associations between objects, contexts and places. Fmr1 KO rats’ ability to discriminate novel from familiar object-place (spatial) and object-place-context (episodic-like) associations was significantly impaired (OP was delayed, and OPC ability did not develop). In the last part of this thesis I examined whether early therapeutic intervention with lovastatin can restore the cognitive deficits I observed. Subjects were fed either a diet containing lovastatin (“lovachow”) or an identically looking control diet, between P29 and P64, and tested in the four spontaneous exploration tasks, previously mentioned. Fmr1 KO rats demonstrated a developmental profile of associative memory indistinguishable from that of WT animals. At P64, lovachow was replaced with standard laboratory chow and the animals were tested 1 and 3 months later. Surprisingly, lovastatin treated Fmr1 KO animals maintained the ability to perform the OPC task even at 3 months after the end of treatment, whereas Fmr1 KO animals on control chow showed no improvement with age. The findings of this work indicate that transgenic rats can complement existing mouse models of FXS, providing valuable insights into the effects of FMRP loss on cognitive function. Furthermore, the results from the treatment study show that not only can lovastatin treatment prevent the emergence of cognitive deficits associated with Fragile X Syndrome but also that lovastatin (and perhaps pharmaceutical interventions more generally) may prevent the developmental deficits in neuronal circuit formation which can be maintained into adulthood.en
dc.contributor.sponsorotheren
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionAsiminas, A., Till, S., Burt, A., Cox, E., Morris, R., Chattarji, S., … Wood, E. (2014). Fmr1 Knockout Rats exhibit abnormal development of episodic memory but normal spatial memory in adulthood. In 699.15/L10. SfN, Washington DC.en
dc.relation.hasversionAsiminas, A., Till, S. M., Osterweil, E. K., Bear, M. F., Chattarji, S., Wyllie, D. J. A., … Wood, E. R. (2016). Lovastatin treatment early in life prevents development of cognitive deficits in a rat model of Fragile X Syndrome. In 392.07 / C24. SfN, San Diego, CA: Society for Neuroscience.en
dc.relation.hasversionAsiminas, A., Till, S., Morris, R., Chattarji, S., Wyllie, D., Kind, P., & Wood, E. (2015). Fmr1 knockout rats express hippocampus-dependent, spatial and episodic-like memory, impairments. In 491.03/E21. SfN, Chicago, IL: Society for Neuroscience.en
dc.relation.hasversionTill, S. M., Asiminas, A., Jackson, A. D., Katsanevaki, D., Barnes, S. A., Osterweil, E. K., … Kind, P. C. (2015). Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS. Human Molecular Genetics, 24(21), 5977–5984. http://doi.org/10.1093/hmg/ddv299en
dc.subjectfragile X syndromeen
dc.subjectFMR1en
dc.subjectKO ratsen
dc.subjectbehavioural neuroscienceen
dc.subjectlovastatinen
dc.titleModelling fragile X syndrome in rats: new directions in translational researchen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dcterms.accessRightsRestricted Accessen
dcterms.accessRightsRestricted Accessen


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