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

03 August 2015

Albino Mouse

©  tiripero

New brain research has mapped a key trouble spot likely to contribute to intellectual disability in Down syndrome. Scientists from the University of Bristol and UCL (University College London) suggest the findings could be used to inform future therapies which normalise the function of disrupted brain networks in the condition.

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.

The current research was made possible by work published around 10 years ago by Dr Victor Tybulewicz of the Francis Crick Institute (previously the Medical Research Council's National Institute for Medical Research) and Professor Elizabeth Fisher of UCL (and Imperial College London at the time).

In a challenging and long-term project, Drs Tybulewicz and Fisher inserted a copy of human chromosome 21 into a mouse to mimic Down syndrome. The resultant mice had learning difficulties, congenital heart defects, and changes in the craniofacial skeleton. Since then the scientists have collaborated with many groups in the UK and around the world to use this strain to better understand what goes wrong in Down syndrome. 

Dr Tybulewicz said: "It is exciting that our original mouse model of Down syndrome is now being used to understand detailed electrophysiological pathways that are perturbed in the condition. Understanding what goes wrong is important in trying to design rational therapies for this complex condition."

In the current study, the team led by the Bristol and UCL scientists used the same mouse strain to show 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 research 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, 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 Fisher 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 paper, Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome, is published in Nature Neuroscience.