The role of the complement system in associative learning and risk for schizophrenia

Reddaway, Jack 2022. The role of the complement system in associative learning and risk for schizophrenia. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Schizophrenia and post-traumatic stress disorder are neuropsychiatric disorders which in part are characterised by impairments in the acquisition and updating of associative memories. Recent genome-wide association studies involving thousands of individuals, have revealed an association between the risk for schizophrenia and genetic variations in the complement system, in particular the genes C4 and CSMD1. However, the reason why aberrances in the complement system increases an individual’s risk for schizophrenia remains unclear. One hypothesis to explain the link between the complement system and schizophrenia is that the complement system drives the adult synaptic plasticity that underlies the recall and extinction of associative memories. In neural development and neurodegenerative diseases, the complement system facilitates synaptic pruning and remodelling. Establishing whether complement mediated plasticity occurs in adulthood and the precise mechanisms by which it occurs, could explain the origins of the associative learning deficits seen in schizophrenia and post-traumatic stress disorder, whilst opening a new avenue for the development or repurposing of drugs to treat these disorders. The experiments in this thesis investigated the relationship between two phases of associative learning: retrieval and extinction, with the changes in the neuroimmune environment in brain regions activated during these phases of learning. We first identified differential activation of hippocampal, pre-frontal cortical and thalamic subregions following contextual fear memory retrieval and extinction, by measuring the protein levels of three immediate early genes: Arc, cFOS and zif268 (Chapter 3). We also reported a decrease in expression of complement system receptor C3aR in the CA1 subregion of the hippocampus following the retrieval of a contextual fear memory (Chapter 4). Following this, we examined whether there were changes in microglial activation following retrieval and extinction which required the development of a novel pipeline to assess morphology across thousands of microglia, in a rapid and non-biased manner (Chapter 5). The successful development of said morphological analysis pipeline revealed decreased microglial activity in the dentate gyrus of the hippocampus following fear memory retrieval when compared to extinction (Chapter 6). These results combine to further our understanding of the role of the neuroimmune system in adult synaptic plasticity and pave the way for future experiments to examine the effects of modulating microglial and complement system activities upon the phases of associative learning.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	27 October 2022
Last Modified:	25 Oct 2023 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/153773

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