1. Synaptic Changes in Neuronal Ceroid Lipofuscinosis
Variant Infantile Batten Disease
Richard Tuxworth, University of Birmingham, UK. r.i.tuxworth@bham.ac.uk
Megan O’Hare & Guy Tear, King’s College London, UK. guy.tear@kcl.ac.uk
What are synapses?
The brain contains billions of nerve cells. Each
makes thousands of connections with
neighbours at structures called synapses.
When an electrical impulse arrives at a
synapse special chemicals are released. These
are called neurotransmitters.
The chemicals cross over to the neighbouring
nerve cell. There are several types of
neurotransmitter chemicals. Some “excite” the
neighbour, other “inhibit” the neighbour.
If enough “exciting” chemicals arrive in a short
space of time, the neighbour will “fire” and an
electrical signal passes along the nerve cell.
1
2 Why are synapses interesting to study?
1. For neurodegenerative diseases
Synapses are one of the first things to
be affected in neurodegeneration
diseases. This happens in all forms of
neurodegeneration including inherited
forms like NCL and late onset forms like
Alzheimer’s disease.
We need to understand what is
happening and why to help design
effective therapies.
2. For developmental disorders
Synapses are changed in some
developmental disorders such as autism.
Changes occur during foetal
development or very early in childhood.
In some forms of autism nerve cells
grow too big and have too many
synapses. We don’t understand why this
leads to the behavioural differences in
autism.
In neurodegenerative diseases with very early onset (like the infantile forms of NCLs) the
changes to synapses must start very early on? Can we see any similarities to the changes
in developmental disorders?
3
How do we study synaptic change?
Many NCL studies use mice to help understand the disease. A mouse
brain is much less complex than a human’s but still contains many
billions of synapses.
As a simpler alternative, we are using
fruit flies to look for synaptic changes
in NCL.
Fruit flies have a much smaller and
simpler nervous system than a mammal
but their nerve cells work identically.
With fruit flies we can also use powerful
genetic tools. This allows us to manipulate
their genes in ways that are not possible
with mice.
4
What are we doing?
We made a fruit fly mutant which does not have the Cln7 gene.
We can are look at one particular nerve and see if the number of
synapses has changed.
We dissect the fruit flies
when they are maggots.
Then we look at the nerves
by microscopy.
The synapses are the small
red dots. More than 5,000
would fit on a pin head.
The rest of the nerve is
shown in green.
We use software to count
the synapses and measure
the size of the nerve.
5
What happens when there is no Cln7 ?
In flies without a Cln7 gene the nerve gets smaller and
the number of synapses decreases.
with
Cln7
without
Cln7
Cln7 lost
then replaced
When we put the gene back the
nerve returns to normal size.
This is an important test
because it shows the change in
nerve size is caused by losing
the Cln7 gene.
We can also see that the nerve no longer works properly.
We are now trying to work out why these things happen.
If we can find that out we will learn a lot about how Cln7
works.
We will also need to see if the size of nerves changes in
mice without any Cln7.
6
Conclusions
Before we can start to develop therapies we need to
understand why neurodegeneration occurs in patients with
Cln7 mutations. But at present we don’t know anything
about what Cln7 does or how it might do it.
We are using a fruit flies as a simple animal model to ask
two key questions:
What does Cln7 do in nerve cells?
What happens to nerve cells when Cln7 is mutated?
If you would like further information about this project
please contact us:
Richard Tuxworth r.i.tuxworth@bham.ac.uk
Guy Tear guy.tear@kcl.ac.uk