03:25pm Saturday 16 December 2017

Scientists identify trouble spot in brain linked to learning difficulties in Down syndrome

 

Down syndrome is the most common genetic cause of intellectual disability, and is triggered by an extra copy of chromosome 21. These findings shed new light on precisely which part of the brain’s vast neural network contribute to problems in learning and memory in Down syndrome which until now, have remained unclear.

Using genetically engineered mice that carry a copy of this additional human chromosome, the researchers showed that increased expression of chromosome 21 genes disrupts the function of key brain circuits involved in learning and memory.

Processing of information in the brain requires accurately coordinated communication between networks of nerve cells, which are wired together in electrical circuits by junctions called synapses. Using high-tech microscopy, nerve cell recordings and maze testing, the researchers showed abnormal structure and function of synapses in the networks of the hippocampus in the mouse model of Down syndrome.

The hippocampus acts as a central hub for learning and memory, allowing us to integrate our past experience with our current context. These functions are underpinned by ’place cells’ — cells that act like the brain’s GPS and form maps of our environment (Professor John O’Keefe, of UCL, was awarded the 2014 Nobel Prize for his discovery of these cells). 

This latest study shows that dysfunction at the input synapses of the hippocampus propagates around hippocampal circuits in the mouse model of Down syndrome, resulting in unstable information processing by place cells and impaired learning and memory. Over the course of a lifetime, even subtle impairments of this type will profoundly influence intellectual abilities.

Dr Matt Jones, lead author of the study and MRC Senior Research Fellow at the School of Physiology and Pharmacology at the University of Bristol, said: “Abnormalities in the hippocampus have been shown before in other mouse models of Down syndrome, but the mouse model we used is a more accurate genetic mimic of the human syndrome. The wiring diagram of the brain is so massively interconnected, we need to consider how even subtle changes in one part of the brain can cause trouble for other nodes of the circuit.”

Dr Jonathan Witton, one of the study’s main authors and also of Bristol’s School of Physiology and Pharmacology, added: “This study further highlights the vulnerability of the hippocampus to increased expression of chromosome 21 genes. Therapies which aim to normalise the function of these disrupted networks may be particularly beneficial as part of the future treatments of Down syndrome.”

Professor Elizabeth Fisher of UCL, who made the mouse model with Dr Victor Tybulewicz of the Francis Crick Institute, said: “It is very important that we work in the most effective and collaborative way to understand what is happening in these mice, so we further our knowledge of human Down syndrome for possible future therapies.”

The collaborative study, funded by the Wellcome Trust and Medical Research Council (MRC), involved researchers from the University of Bristol, UCL, Open University, University of Oxford, and the Francis Crick Institute, London. 

Paper

Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome by J Witton et al in Nature Neuroscience.

 

Further information

The Wellcome Trust

The Wellcome Trust is a global charitable foundation dedicated to improving health. We support bright minds in science, the humanities and the social sciences, as well as education, public engagement and the application of research to medicine. Our investment portfolio gives us the independence to support such transformative work as the sequencing and understanding of the human genome, research that established front-line drugs for malaria, and Wellcome Collection, our free venue for the incurably curious that explores medicine, life and art.www.wellcome.ac.uk

Medical Research Council

The Medical Research Council is 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. Thirty-one 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


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