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Biochemical analysis of genetically-modified mice with learning and memory phenotypes.

Plattner, F.; (2006) Biochemical analysis of genetically-modified mice with learning and memory phenotypes. Doctoral thesis , University of London. Green open access

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Abstract

Recent advances in molecular genetics have enabled generation of sophisticated genetically-modified mouse models to study specific molecules and their biological function in vivo. Here, I investigated biochemical changes in two different genetically-modified mouse lines with previously described learning and memory phenotypes. Firstly, I analysed biochemical changes in a mouse line carrying a threonine to alanine point mutation at Thr286 of alpha Ca2+/calmoduline-dependent kinase II (aCaMKII), which disenables this phosphorylation site. Autophosphorylation at Thr286 switches aCaMKII into an autonomous activity mode. The T286A mutant mice displayed changes in basal phosphorylation levels. In order to study biochemical changes after activity-dependent synaptic potentiation, an in vivo long-term potentiation (LTP) approach was established and validated by assessing activity-dependent changes in phosphorylation levels of well-characterised marker molecules including synapsin I and NR2B. Both aCaMKII and pCaMKII exhibited elevated levels of autophosphorylation after LTP stimulation in hippocampal area CA1 and dentate gyrus (DG). This finding indicates that pCaMKII may compensate for the loss of autonomous aCaMKII activity in T286A mutants. Furthermore, induction of LTP triggered phosphorylation of glycogen synthase kinase 3 (GSK3) at its inhibitory site suggesting a role for GSK3 in synaptic plasticity. Secondly, I investigated a transgenic (TG) mouse line expressing the cyclin-dependent kinase (Cdk5) activator protein, p25, a protein previously linked to some aspects of Alzheimer's disease (AD). The forebrain restricted expression of p25 started postnatally and stayed constant throughout the life-span of the TG mice. The expression of p25 triggered constitutive over-activation of Cdk5 in the TG mice. The p25 TG mice displayed age-dependent hyperphosphorylation of the microtubule-associated protein tail and age-dependent alterations in the processing of amyloid precursor protein (APP). Furthermore, p25-induced over-activation of Cdk5 led to inhibition of GSK3. This negative regulation of GSK3 was lost in aged p25 TG mice and correlated with the increased tau hyperphosphorylation. The levels of tau phosphorylation in aged p25 mice were reduced after treatment with lithium, an inhibitor of GSK3. These results indicate that GSK3 directly mediates tau hyperphosphorylation, whereas Cdk5 acts indirectly via inhibitory control of GSK3.

Type: Thesis (Doctoral)
Title: Biochemical analysis of genetically-modified mice with learning and memory phenotypes.
Identifier: PQ ETD:591986
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/1444677
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