Need, Anna Christina;
(2004)
Molecular genetic studies of hippocampal learning and memory in the mouse.
Doctoral thesis (Ph.D.), University College London (United Kingdom).
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Abstract
Mouse molecular genetics has become a powerful approach to the understanding of complex behaviours such as learning and memory (L and M). I have considered how point mutations, region-restricted mutations and the study of gene-environment interactions can clarify the roles of individual genes in hippocampal L and M. PI3 kinase has been implicated in L and M, but the role of particular isoforms is not clear. I have investigated p110δD910A point mutants in the Morris water maze, and found that this isoform is not required for spatial L and M. Recent work has indicated that P13Kα and P13Kβ are more abundant in the hippocampus than PI3Kδ, but global knockouts of P13Kα and P13Kβ die in utero. In order to test their role in hippocampal L and M, mutations of P13Kα and P13Kβ could be restricted to the hippocampus using hippocampus-restricted Cre recombination. However, it is first necessary to produce a mouse line that has Cre recombination in the entire hippocampus, but not in other brain regions. Using a knock-in strategy, I have inserted a Cre cassette into the 3' untranslated region of the mouse mineralocorticoid receptor gene. The Cre is driven by an internal ribosome entry site (IRES) derived from fibroblast growth factor 2, and has high CNS activity. The combination of the expression of the mineralocorticoid receptor, and the activity of the IRES, should result in Cre recombination in all areas of, but restricted to, the hippocampus. Currently, mice used in behavioural experiments are housed under deprived conditions, and this could lead to a misrepresentation of the normal function of genes in hippocampal L and M investigations. I examined the effect of environmental enrichment on two mouse lines that showed L and M impairments in earlier reports. I found that the L and M deficits shown by the Kvβ1.1-/- mutants were rescued, but that αCaMKII1286A mutants remained impaired despite intensive pre-and post-weaning enrichment.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D. |
| Title: | Molecular genetic studies of hippocampal learning and memory in the mouse |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | (UMI)AAI10014336; Biological sciences; Hippocampus |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10103383 |
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