Genes linked to autism and schizophrenia are only switched on during the early stages of brain development, according to a study in mice led by researchers at the University of Oxford.
This new study adds to the evidence that autism and schizophrenia are neurodevelopmental disorders, a term describing conditions that originate during early brain development.
The researchers studied gene expression in the brains of mice throughout their development, from 15-day old embryos to adults, and their results are published today in Proceedings of the National Academy of Sciences.
The study is a collaboration between researchers from the University of Oxford, King's College London and Imperial College London, and was funded by the Medical Research Council and the Wellcome Trust.
The research focused on cells in the 'subplate', a region of the brain where the first neurons (nerve cells) develop. Subplate neurons are essential to brain development, and provide the earliest connections within the brain.
'The subplate provides the scaffolding required for a brain to grow, so is important to consider when studying brain development,' says Professor Zoltán Molnár, senior author of the paper from the University of Oxford, 'Looking at the pyramids in Egypt today doesn't tell us how they were actually built. Studying adult brains is like looking at the pyramids today, but by studying the developing brains we are able to see the transient scaffolding that has been used to construct it.'
The study shows that certain genes linked to autism and schizophrenia are only active in the subplate during specific stages of development. 'The majority of the autism susceptibility genes are only expressed in the subplate of the developing mouse brain,' explains Dr Anna Hoerder-Suabedissen, who led the study at the University of Oxford, 'Many can only be found at certain stages of development, making them difficult to identify at later stages using previous techniques.'
The group were able to map gene activity in full detail thanks to powerful new methods which allowed them to dissect and profile gene expression from small numbers of cells. This also enabled them to identify the different populations of subplate neurons more accurately.
Subplate neurons were first discovered in the 1970s by Professors Ivica Kostović and Pasko Rakic of Yale University.
'I am excited to see tangible genetic links supporting, even indirectly, the idea of a possible role of the transient embryonic subplate zone in the origin of disorders such as autism and schizophrenia,' says Professor Rakic, 'If this is possible to show in mice, where the subplate is relatively small, it is likely to be even more pronounced in humans, where it is much more evolved.
'The study from Professor Molnár's group at Oxford may be the first step toward finding more such links in the future and opens the possibility of directly examining the roles of genetic variation and exposure to various environmental factors in animal models.'
Professor David Edwards, Director of the Centre for the Developing Brain at King's College London, and co-author of the paper, said: 'Using advanced techniques we have been able to define the biochemical pathways that are important during a particular phase of brain development. It has been suspected for a long time that if the development of the cortex is disrupted by genetic abnormalities or environmental stress (such as prematurity) this would have long-lasting adverse effects on brain development and could lead to problems like ADHD or autism. This study defines genes that are important in mice at this critical period and this does indeed seem to include genes known to predispose to autism and schizophrenia. It focuses attention even more firmly on early brain development as a cause of these distressing neuropsychological problems.'
Professor Hugh Perry, chair of the Medical Research Council's Neuroscience and Mental Health Board, said: 'By being able to pinpoint common genetic factors for neurological conditions such as autism and schizophrenia, scientists are able to understand an important part of the story as to why things go awry as our brains develop. The Medical Research Council's commitment to a broad portfolio of neuroscience and mental health research places us in a unique position to respond to the challenge of mental ill health and its relationship with physical health and wellbeing.'
Notes to Editors
* The University of Oxford's Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK's top-ranked medical school.
From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.
A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.
* King's College London is one of the top 30 universities in the world (2011/12 QS World University Rankings), and the fourth oldest in England. A research-led university based in the heart of London, King's has nearly 23,500 students (of whom more than 9,000 are graduate students) from nearly 140 countries, and some 6,000 employees. King's is in the second phase of a £1 billion redevelopment programme which is transforming its estate.
King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.
King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe; no university has more Medical Research Council Centres. King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: www.kingshealthpartners.org.
* Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.
Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges. In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK's first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.
* Over the past century, The Medical Research Council has been at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers' money in some of the best medical research in the world across every area of health. Twenty-nine MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed.
Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms. www.mrc.ac.uk
The MRC Centenary Timeline chronicles 100 years of life-changing discoveries and shows how MRC research has had a lasting influence on healthcare and wellbeing in the UK and globally, right up to the present day. www.centenary.mrc.ac.uk
* The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests. www.wellcome.ac.uk
Journal
Proceedings of the National Academy of Sciences