Exploring the relationship between schizophrenia risk and adult hippocampal plasticity

Wellard, Natalie 2022. Exploring the relationship between schizophrenia risk and adult hippocampal plasticity. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Bleuler was the first to identify abnormal associations as one of the basic symptoms of schizophrenia, which has since been extensively demonstrated. Consolidation and retrieval of contextual fear conditioning (CFC) have been shown elicit differential patterns of gene expression in the hippocampus. Large-scale genomic studies have identified common and rare variants that are enriched in patients with schizophrenia, and these have been shown to impact genes involved in synaptic plasticity and associative learning. Here, CFC was used to explore how gene expression underlying associative learning may be associated with schizophrenia risk variants. In Chapter 3, RNA sequencing was used to detect gene expression changes following retrieval and extinction of conditioned fear. Contrary to previous work, few genes were found to be significantly differentially expressed, and there was no enrichment of learning-related gene sets in schizophreniaassociated genetic variation. Next, using publicly available data, I demonstrated that gene-sets derived from a functional LTP experiment were significantly enriched in schizophrenia-associated risk variants, particularly genes expressed in CA1 excitatory neurons, as determined using cell-type specific TRAP-sequencing (Chapter 4). Finally, given that LTP processes are thought to underlie consolidation of fear memories, I used TRAP-seq to explore the gene expression profile of excitatory hippocampal neurons following acquisition of CFC. I found significantly more genes differentially expressed in excitatory hippocampal neurons compared to bulk RNA-seq, mirroring the results of Chapter 4. Genes that were significantly down-regulated 5- hours after acquisition of CFC, during the consolidation window, were enriched in immune processes, suggesting a down-regulation of the immune system during the consolidation of contextual fear. However, no enrichment in risk variants associated with schizophrenia were found. These results build on previous literature examining gene expression following consolidation and retrieval of conditioned fear, and demonstrate the advantages of using cell-type specific sequencing in such experiments.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	21 November 2022
Last Modified:	06 Jan 2024 03:36
URI:	https://orca.cardiff.ac.uk/id/eprint/154342

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