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The birth of nerves
Basic bioscience of neurons opens avenues for epilepsy research
14 July 2011
Scientists studying the fundamental biology of nerve cells (neurons) in fruit flies have pinpointed aspects of neuronal activity relevant to neurogenesis - the process of neural development that underpins growth, learning and healthy ageing in animals.
The work also confirmed that insect larvae can be an acceptable animal model for research on the electrophysiology of neurons, which can reduce the use of mammals (ref 1). The work may also benefit many other avenues of research because the actions of nerve cells are critical determinants of healthy development and behaviour of many organisms.
A fruit fly motor neuron that the researchers used to understand the electrophysiology of the fly central nervous system. Image: R. Baines
Furthermore, the findings have direct relevance to future research into the causes and development of epilepsy. Experiments showed that mutant flies destined to exhibit epileptic-like seizures could be effectively cured by treating them with an established antiepileptic drug when they were early embryos (ref 2).
In recent years, researchers have been experimenting with alternative animal models to study neurons. Instead of rats or mice, Professor Richard Baines at the University of Manchester, who led the research, and his colleague Dr Richard Marley used fruit fly (Drosophila melanogaster) mutants. The simpler fly nervous system contains far fewer neurons and is relatively easier to study than mammals. In addition, the genetics of the organism is well understood: it has been estimated that the fly genome contains 75% of all human disease genes.
A third instar (moult) Drosophila larva used for the seizure tests. Image: R. Baines
"My lab is unique in being able to use sophisticated techniques such as patch clamp recording from neurons in flies to obtain a very detailed picture of the underlying causes of seizure in these insects," says Baines. The patch clamp technique is a method that allows scientists to measure the activity of individual channels by which charged molecules (ions)enter or leave cells.
For the first part of his study, Baines used slamdance (sda) Drosophila larvae (already used by other laboratories) which possess a mutation in the fly version of human aminopeptidase, a glycoprotein that is widely expressed in animal tissues, including the nervous system. Exposing sda larvae to a mild electric shock to induce a seizure, the scientists demonstrated that the current mediated by sodium channels in nerve cells, which initiate the nervous impulse that travels along the length of a nerve by a series of action potentials (see diagram), is increased in sda flies and causes the seizure.
A patch clamp recording reveals transitions between two conductance states (high, low) of a single ion channel: closed (at top) and open (at bottom). Image Theresa Knott
"Functionally, this current when increased is expected to cause a neuron to fire more action potentials than it would normally do in response to stimulation," says Baines. "Seizures in both humans and Drosophila exhibit sufficient parallels to implicate that the underlying neuronal abnormalities are highly similar."
Anti-epileptic drugs (AEDs) designed for humans such as phenytoin duly reduced seizures in the flies by specifically reducing the sodium nerve channel current targeted by Baines.
I am the fly
Baines and his colleague's hypothesis was that increased activity in the slamdance (fruit fly) mutant leads to altered neurogenesis that, later in life, increases the chance of seizure. So they went a step further by feeding the AED phenytoin to mated fruit flies. "Our idea here was to effect transfer of a small amount of anti-epileptic drug to the developing embryo," says Baines. "Fly mothers, like chickens, put a lot of nutrient into the egg to support the developing embryo."
Results showed that the larvae showed vastly reduced seizures and were, as Baines says, "effectively cured" of epilepsy. "By dosing the mother with drug we showed in the study that a small amount is transferred to the egg," says Baines. "They still have the same gene mutation but its contribution to seizure has been overcome."
Baines says that the drug is likely acting on neurogenesis in the embryo. "By having the drug present at the earliest stages of neurogenesis we hoped to constrain this increased activity and allow the nervous system to develop normally. Our results are consistent with this outcome."
- Increased persistent sodium current contributes to seizure in the slamdance bang-sensitive Drosophila mutant
- Slamdance: seizing a fly model for epilepsy
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