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.