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Vlincl tuxworth


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Vlincl tuxworth

  1. 1. Synaptic Changes in Neuronal Ceroid Lipofuscinosis Variant Infantile Batten Disease Richard Tuxworth, University of Birmingham, UK. Megan O’Hare & Guy Tear, King’s College London, 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 Guy Tear