Modelling of schizophrenia associated 3q29 deletion and duplication syndrome using human IPSCs

Trabzonlu, Kubra 2025. Modelling of schizophrenia associated 3q29 deletion and duplication syndrome using human IPSCs. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The 3q29 deletion and duplication syndromes, caused by a 1.7 Mb copy number variation at the 3q29 locus, are rare genomic disorders associated with over a 40-fold increased risk of schizophrenia. This locus encompasses 21 protein-coding genes involved in cytoskeletal organization, cell apoptosis, synaptic signalling, neuronal transmission, and synaptogenesis—functions commonly disrupted in neurodevelopmental disorders. Modelling these syndromes using patient-derived induced pluripotent stem cells (IPSCs) offers a unique opportunity to uncover cellular mechanisms underlying shared neuropsychiatric risk. In this study, I hypothesised that deletion or duplication of 3q29 deletion leads aberrant synaptogenesis and network activity. For this purpose, IPSCs from individuals with 3q29 deletion or duplication were differentiated into cortical neurons to investigate early neurodevelopmental trajectories. Both mutations led to significant alterations in early and late neuronal development, including increased expression of neural progenitor, neuronal, and synaptic markers, as well as elevated synaptic puncta density. Additionally, changes were observed in lower layer cortical identity and excitatory-inhibitory balance, alongside dysregulation of calcium channel and receptor genes. Functional assays revealed enhanced calcium activity and disrupted calcium homeostasis in mutant neuronal cultures. Multielectrode array (MEA) analysis demonstrated hyperactive and hypersynchronous neuronal network activity in both 3q29 deletion and duplication lines. Notably, deletion neurons exhibited early maturation and synchrony, with duplication neurons reaching similar levels within a month—both surpassing control cultures. Proteomic analysis identified synapse-related pathways as top enriched categories, with LGI1 emerging as a highly upregulated protein in both conditions. Given LGI1’s interaction with Kv1.1 channels, pharmacological modulation using Kv1.1-specific agonists was preliminary tested and reduced network hyperactivity. However, further studies are required to refine and validate these therapeutic candidates. These findings provide critical insights into the cellular and molecular mechanisms disrupted by 3q29 deletion and duplication, offering a deeper understanding of the core pathophysiology underlying neurodevelopmental and neuropsychiatric phenotypes. This work lays the foundation for future therapeutic strategies targeting shared pathways in schizophrenia and related disorders.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	30 April 2026
Date of Acceptance:	30 April 2026
Last Modified:	05 May 2026 13:40
URI:	https://orca.cardiff.ac.uk/id/eprint/186704

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