Epigenetic mechanisms of behavioural, placental and cognitive impairment in a neurodevelopmental model for schizophrenia
Lead Research Organisation:
University of Manchester
Department Name: School of Health Sciences
Abstract
A fundamental question in disease research is how stressors experienced during critical developmental periods influence the genesis or 'programming' of adult disease (Estes & McAllister 2016). In particular, stressors experienced during pregnancy have effects on the propensity to develop cognitive disorders in the offspring (Knuessel et al. 2014). Whether this relates to changes directly affecting brain development in utero, or altered maternal behaviour, or a combination of these, is unclear. Further, the mechanisms underlying such effects remain poorly defined.
Maternal stressors cause epigenetic modifications (DNA methylation and histone modifications) in offspring brain and placental tissue, which are likely to be key candidate mechanisms leading to altered gene expression, evoking developmental changes in the brain that result in cognitive and behavioural impairment (Akbarian 2014).
Further, the placenta plays a crucial role in maternal-fetal interactions and the modulation of fetal adaptive responses that may lead to increased propensity to disease development later in life. Placental development and function is affected by maternal stressors, but how this links to cognitive impairment in offspring is unclear. Recent genome-wide association studies have identified risk factor genes for schizophrenia which adversely affect placentation (Ursini et al. 2017). This may explain the high level of early life complications in patients who later develop schizophrenia. We predict that epigenetic mechanisms mediate the effects of maternal stressors on placental function and hence cognitive development.
The proposed project seeks to investigate epigenome x environment interactions that link to schizophrenia development. We will use a multidisciplinary approach to map functional changes along a developmental timeline that links placental morphological development to offspring behavioural traits. Evaluation of placental morphological development, molecular array studies, epigenomic and histological analyses in brain and placenta together with parent-offspring behavioural interactions, cognitive and behavioural analyses in a rodent neurodevelopmental model for schizophrenia will be conducted. The project therefore offers broad scientific training covering mammalian disease and behavioural research, histology, physiology, molecular biology, epigenetic and gene expression analyses.
Maternal stressors cause epigenetic modifications (DNA methylation and histone modifications) in offspring brain and placental tissue, which are likely to be key candidate mechanisms leading to altered gene expression, evoking developmental changes in the brain that result in cognitive and behavioural impairment (Akbarian 2014).
Further, the placenta plays a crucial role in maternal-fetal interactions and the modulation of fetal adaptive responses that may lead to increased propensity to disease development later in life. Placental development and function is affected by maternal stressors, but how this links to cognitive impairment in offspring is unclear. Recent genome-wide association studies have identified risk factor genes for schizophrenia which adversely affect placentation (Ursini et al. 2017). This may explain the high level of early life complications in patients who later develop schizophrenia. We predict that epigenetic mechanisms mediate the effects of maternal stressors on placental function and hence cognitive development.
The proposed project seeks to investigate epigenome x environment interactions that link to schizophrenia development. We will use a multidisciplinary approach to map functional changes along a developmental timeline that links placental morphological development to offspring behavioural traits. Evaluation of placental morphological development, molecular array studies, epigenomic and histological analyses in brain and placenta together with parent-offspring behavioural interactions, cognitive and behavioural analyses in a rodent neurodevelopmental model for schizophrenia will be conducted. The project therefore offers broad scientific training covering mammalian disease and behavioural research, histology, physiology, molecular biology, epigenetic and gene expression analyses.