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The impact of the interaction between Neuroligin3 and CYFIP1 on phenotypes associated with Autism Spectrum Disorders

Sledziowska, Monika Teresa 2020. The impact of the interaction between Neuroligin3 and CYFIP1 on phenotypes associated with Autism Spectrum Disorders. PhD Thesis, Cardiff University.
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Abstract

Autism spectrum disorders (ASD) are characterised by alterations in behaviour, brain structure and molecular processes. The underlaying genetic aetiology is complex, with many genes linked to ASD. However, there might be convergence in the function of protein products of these genes, leading to the characteristic phenotypes associated with ASD. The role of two proteins associated with ASD, Neuroligin3 and CYFIP1, in establishing these phenotypes was investigated. The interaction between them was confirmed, in neurons, in vivo. Additionally, several other proteins associated with ASD were found to interact with Neuroligin3, indicating that they might contribute to the same biological pathway. Interestingly, the interactors of Neuroligin3 differed between neurons and glia, suggesting that they were cell population specific. Double mutant mice lacking Nlgn3 and heterozygous for Cyfip1 were generated to investigate the impact of the Neuroligin3/CYFIP1 interaction on mouse behaviour, dendritic spine density and RNA expression. The double mutant mice phenocopied their littermates with Nlgn3 deletion in their hyperactivity. However, motor learning, which is impaired in males heterozygous for Cyfip1, was restored in the double mutant males, this finding suggesting that Neuroligin3 could inhibit the function of CYFIP1 at the molecular level. Two other parameters modulated the effect of these genetic mutations on behaviour: sex of the mice and the social environment in which they were reared. There might be an increase of dendritic spine density in the motor cortex in the double mutants, but this effect did not extend to the visual cortex, suggesting that increased genetic load led to region-specific alterations in this parameter. On the other hand, the RNA expression in the hippocampus was only affected by the Nlgn3 deletion and was again modulated by the social environment. In particular, the transcriptome of WT and Nlgn3 knockout males differed between those housed with littermates of the same and of different genotype. In conclusion, the interaction between Neuroligin3 and CYFIP1 affected the behaviour of mice, the dendritic spine density in the motor cortex and the transcriptome in the hippocampus and this effect was further modulated by sex of the mice and their social environment. These findings support the fact that ASD is likely to result from complex interaction between genes and the environment.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history > QH301 Biology
Date of First Compliant Deposit: 17 February 2021
Last Modified: 18 Feb 2021 08:08
URI: https://orca.cardiff.ac.uk/id/eprint/138602

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