The role of the psychiatric risk-associated gene Cacna1c and sex in hippocampal dependent cognition

Mawson, Eleanor 2024. The role of the psychiatric risk-associated gene Cacna1c and sex in hippocampal dependent cognition. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Psychotic and mood disorders such as schizophrenia, bipolar disorder and depression affect a substantial proportion of individuals and constitute a considerable degree of years lived with disability. Common risk single-nucleotide polymorphisms (SNPs) of the CACNA1C gene, which encodes the a1c subunit of Ltype voltage gated calcium channels (LTCCs), have been robustly associated with all three disorders. Biological sex also has a major impact on risk for psychotic and mood disorders. However, the degree to which risk SNPs differentially impact sexes is not well understood. We have investigated the effects of low Cacna1c gene dosage and sex using contextual fear conditioning behaviours known to depend upon the hippocampus. Both Cacna1c heterozygosity and sex showed independent effects on hippocampal dependent associative fear learning by affecting the integration of previously learned information in contextual fear processing. Cacna1c+/- animals also showed increased expression of genes with functions related to neuroimmune processing and the brain extracellular matrix (ECM), and sex differences were seen in genes with functions related to epigenetic histone protein modifications, among others. Cacna1c heterozygosity also appears to affect males and females similarly, however, sex differences in the impact of low Cacna1c gene dosage were observed in both behavioural and (hypothalamic-pituitaryadrenal) HPA-axis response measures. These findings suggest that CACNA1C risk variants may confer increased risk for psychotic and mood disorders by affecting contextual associative fear learning processes mediated by the hippocampus, possibly via affecting neuroimmune, brain ECM and HPA-axis processes. Although interactions between sex and Cacna1c genotype were limited, the findings suggest that the neurobiological processes implicated in CACNA1C risk SNPs may be sexually dimorphic.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	28 January 2025
Last Modified:	28 Jan 2025 16:51
URI:	https://orca.cardiff.ac.uk/id/eprint/175690

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