Investigating the role of striatal medium spiny neurons in a human iPSC model of neurodevelopmental disorders

Petter, Olena 2024. Investigating the role of striatal medium spiny neurons in a human iPSC model of neurodevelopmental disorders. MPhil Thesis, Cardiff University. Item availability restricted.

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Abstract

Neurodevelopmental and psychiatric disorders such as schizophrenia and autistic spectrum disorder stem from changes in strictly controlled mechanisms overseeing brain development. These conditions are characterised by the high variability of symptoms, such as impaired sensor, motor and cognitive functions. This thesis investigates the impact of 16p11.2 copy number variants (CNVs) on medium spiny neuron (MSN) development. The primary objective is to identify pathological changes on the cellular level in MSNs derived from individuals carrying deletions or duplications of 16p11.2 locus. To achieve this, an approach was used to generate CNV carrier-specific induced pluripotent stem cells (iPSCs) and investigate how 16p11.2 CNVs affect MSN differentiation. This research revealed that 16p11.2dup iPSCs exhibit accelerated neuronal differentiation, while 16p11.2del iPSCs show increased progenitor proliferation and delayed maturation, highlighting the critical role of 16p11.2 genes in neurogenesis. A temporal expression analysis of the genes from the 16p11.2 region allowed us to observe the timings of normal function of these genes in MSN differentiation. The findings indicate that disruptions in gene dosage at the 16p11.2 locus can significantly alter neurodevelopmental processes, potentially contributing to the phenotypic variability observed in NDDs. In conclusion, this thesis advances our understanding of the molecular mechanisms by which 16p11.2 CNVs disrupt neurogenesis, providing a foundation for future studies and targeted therapies for neurodevelopmental disorders.

Item Type:	Thesis (MPhil)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	22 May 2025
Last Modified:	22 May 2025 11:03
URI:	https://orca.cardiff.ac.uk/id/eprint/178392

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