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Modelling the neuropathology of Ehmt1 haploinsufficiency

Davis, Brittany 2014. Modelling the neuropathology of Ehmt1 haploinsufficiency. PhD Thesis, Cardiff University.
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Abstract

EHMT1 is a gene that encodes an epigenetic regulator important for normal brain development. Disruption in EHMT1 is associated with a number of neurodevelopment and psychiatric conditions, like schizophrenia, Autism Spectrum Disorders, developmental delays and intellectual disabilities. In order to help elucidate the role of Ehmt1 in cortical development two models are examined: the differentiation of mouse pyramidal neurons lacking one copy of the gene and a forebrain-specific Ehmt1-haploinsufficient mouse model. Ehmt1+/- cells demonstrated changes in cell cycle, with significant differences in proliferation rates at embryonic stem cell and neural progenitor stages. Ehmt1+/- cells demonstrated significantly different transcriptional profiles in early and late stages of progenitor development, which suggested these cells, underwent precocious differentiation. In addition, the dysregulation of mRNA expression in a number of the Nrsf/Rest repressor complex members and Rest target genes was found; and Ehmt1+/- cells did not survive as post-mitotic neurons. The forebrain-specific Ehmt1-haploinsufficient mouse model, Ehmt1D6Cre/+, importantly showed normal Mendelian birth ratios, survival, motor coordination and function and no gross morphological changes in brain structure. However, these mice demonstrated differences in activity levels and anxiety-related measurements; deficits in sensorimotor gating and object recognition; and significant differences in a number of electrophysiological measurements, including abnormal event-related neural responses in the cortex and high frequency oscillatory patterns. Taken together, these data suggest that Ehmt1 expression is important for normal pyramidal development and Ehmt1 haploinsufficiency throughout development manifests cortical dysfunction, which leads to marked behavioural and electrophysiological abnormalities.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > Q Science (General)
R Medicine > RB Pathology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: developmental and psychiatric disorders, histone methylation, epigenetics, cortical development
Funders: Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Last Modified: 14 May 2016 01:30
URI: http://orca.cf.ac.uk/id/eprint/73068

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