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Title: The role of synapse-associated protein 102 in postsynaptic signalling, synaptic plasticity and learning
Author: Cuthbert, P. C.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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This dissertation describes a gene targeting approach to elucidate the function of SAP102 in mice. A DNA cloning technique using homologous recombination in bacteria was adapted and found to provide a highly efficient and flexible tool for the production of large numbers of varied mutation types in different loci of the mouse genome. Targeting vectors were generated for the introduction of three different mutations into the SAP102 locus: a constitutive knockout; a reporter gene knock-in and a conditional mutation. SAP102 knockout mice were generated and found to be viable and fertile with grossly normal adult brain morphology. Behavioural tests uncovered a deficit in spatial learning in the watermaze which, in contrast to PSD-95 mutant mice, could be overcome with training. SAP102 mice exhibited a specific, frequency-dependent deficit in NMDAR-mediated hippocampal synaptic plasticity, a possible physiological mechanism for learning, while basal synaptic function and NMDAR conductance were unaffected. A screen of postsynaptic protein phosphorylation states in SAP102 mutant mice showed a specific increase in phosphorylation of extracellular signal-related kinase (ERK), part of the MAP kinase signalling pathway. Targeted mutations in SAP102 and PSD-95 were utilised to explore the functional relationship between the two proteins. A SAP102/PSD-95 double mutation was lethal, indicating an important role for these proteins during development. SAP102 is crucial for normal postsynaptic signalling, synaptic plasticity and learning and begins to shed light on the differential roles of NMDAR-associated MAGUKs in coordinating intracellular responses to postsynaptic activation. SAP102 null mice may prove a useful tool in discovering and testing treatments for human learning disability.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available