The association of hippocampal long-term potentiation-induced gene expression with genetic risk for psychosis

Wellard, Natalie L., Clifton, Nicholas E. ORCID: https://orcid.org/0000-0003-2597-5253, Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222, Thomas, Kerrie L. ORCID: https://orcid.org/0000-0003-3355-9583 and Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009 2024. The association of hippocampal long-term potentiation-induced gene expression with genetic risk for psychosis. International Journal of Molecular Sciences 25 (2) , 946. 10.3390/ijms25020946

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Abstract

Genomic studies focusing on the contribution of common and rare genetic variants of schizophrenia and bipolar disorder support the view that substantial risk is conferred through molecular pathways involved in synaptic plasticity in the neurons of cortical and subcortical brain regions, including the hippocampus. Synaptic long-term potentiation (LTP) is central to associative learning and memory and depends on a pattern of gene expression in response to neuronal stimulation. Genes related to the induction of LTP have been associated with psychiatric genetic risk, but the specific cell types and timepoints responsible for the association are unknown. Using published genomic and transcriptomic datasets, we studied the relationship between temporally defined gene expression in hippocampal pyramidal neurons following LTP and enrichment for common genetic risk for schizophrenia and bipolar disorder, and for copy number variants (CNVs) and de novo coding variants associated with schizophrenia. We observed that upregulated genes in hippocampal pyramidal neurons at 60 and 120 min following LTP induction were enriched for common variant association with schizophrenia and bipolar disorder subtype I. At 60 min, LTP-induced genes were enriched in duplications from patients with schizophrenia, but this association was not specific to pyramidal neurons, perhaps reflecting the combined effects of CNVs in excitatory and inhibitory neuron subtypes. Gene expression following LTP was not related to enrichment for de novo coding variants from schizophrenia cases. Our findings refine our understanding of the role LTP-related gene sets play in conferring risk to conditions causing psychosis and provide a focus for future studies looking to dissect the molecular mechanisms associated with this risk.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	MDPI
ISSN:	1661-6596
Date of First Compliant Deposit:	9 February 2024
Date of Acceptance:	11 January 2024
Last Modified:	27 Feb 2024 12:39
URI:	https://orca.cardiff.ac.uk/id/eprint/166218

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