Characterisation of neurodevelopmental disorder and ageing phenotypes in transgenic mouse and fruit fly models of Neurexin1 dysfunction

Hughes, Rebecca and Dawson, Neil and Broughton, Susan (2019) Characterisation of neurodevelopmental disorder and ageing phenotypes in transgenic mouse and fruit fly models of Neurexin1 dysfunction. PhD thesis, Lancaster University.

Text (2019hughesphd)
2019hughesphd.pdf - Published Version
Download (5MB)

Abstract

Heterozygous (Hz) deletions in Neurexin1 (NRXN1), which encodes a presynaptic cell adhesion protein, increase the risk of developing Schizophrenia (Sz) and Autistic Spectrum Disorder (ASD). In addition, there is accumulating evidence for the accelerated ageing hypothesis of Sz. Using a transgenic mouse model of Neurexin1α heterozygosity (Nrxn1α Hzmice) and a fly model overexpressing Neurexin1 (Nrx-1), the current study aimed to investigate: (1) whether Nrxn1α heterozygosity causes Sz or ASD relevant phenotypes (behaviour and cognition) and endophenotypes (brain function) in mice, and whether these changes are temporally regulated across adult development, and (2) whether Nrx-1 dysfunction affects life span and behavioural senescence using Drosophila melanogaster as a model organism. It was found that Nrxn1α Hz mice show hyperlocomotor activity and increased anxiety-like behaviour in the Open Field (OF) test, deficits in recognition memory in the Novel Object Recognition Task (NORT), and defective reversal learning in a Cognitive Flexibility Task (CFT). In parallel, Nrxn1α Hz mice also show decreased cerebral metabolism in the frontal lobe and increased metabolism in dopaminergic and serotonergic system brain regions, as measured by 14C-2-Deoxyglucose (14C-2DG) functional brain imaging. Furthermore a selection of phenotypes and endophenotypes seen in Nrxn1α Hz mice are differentially regulated across adult development, including enhanced associative learning and increased cerebral metabolism in the Dorsal Raphé. In Drosophila melanogaster, Nrx-1 overexpression (in P{XP}Nrxd08766 flies) induced a small but significant life span extension and significant reductions in behavioural senescence as measured by the Exploratory Walking (EW) assay. Furthermore P{XP}Nrxd08766 flies showed sex-dependant alterations in locomotor activity and sleep structure. In conclusion, Nrxn1α heterozygosity in mice caused phenotypes and endophenotypes that are relevant to both Sz and ASD, including deficits in cognitive flexibility and hypofrontality. Some of these measures were differentially regulated across adult development. In addition, increased expression of Nrx-1 reduced measures of ageing in the fly. Overall these data suggest that Nrxn1α Hz mice provide a useful translational model for drug discovery. In addition, some effects of Neurexin may be mediatiated through the modification of ageing processes, although further research is required to confirm this.