Award details

Characterisation of seizure-suppressor genes in Drosophila

Reference	BB/E000029/1
Principal Investigator / Supervisor	Professor Richard Baines
Co-Investigators / Co-Supervisors
Institution	The University of Manchester
Department	Life Sciences
Funding type	Research
Value (£)	292,537
Status	Completed
Type	Research Grant
Start date	01/04/2007
End date	31/03/2010
Duration	36 months

Abstract

Epilepsy is a significant clinical disorder that affects 1-2% of the population. Currently up to one third of patients respond poorly to anti-epileptic drugs underlining the need for the development of novel pharmaceuticals. In order to develop new drugs, however, additional targets must first be identified. The existence of seizure-sensitive mutants of the fruitfly, Drosophila melanogaster, is significant in that it opens the way for the identification of such new targets. Seizure in adult flies shares many characteristics with seizure in humans and considerable characterisation shows that the fly is a suitable model system in which to further understand human epilepsy. The recent demonstration that certain genes, when upregulated, act as seizure-suppressors in the fly offers the exciting possibility of new treatments for humans. Characterisation of the mechanisms of action of the protein-products of these genes is, however, limited in the adult fly. This proposal aims to use a recently developed preparation of the Drosophila larval CNS which is suited to sophisticated electrophysiology that is necessary to study seizure and is suppression in the CNS. Moreover, synaptic transmission at identified central synapses is aberrant in the larvae of seizure-sensitive mutants providing an assayable system in which to examine seizure-suppression. This study will characterise aberrant synaptic transmission in a range of seizure-sensitive larvae and will determine the extent of rescue following the expression of known seizure-suppressor genes. Both the timing and localisation to specific neuronal subpopulations will be determined using the GAL-4/UAS expression system. The outcome of this work will be a better understanding of the mechanisms of action of known seizure-suppressors in the fly, information that may provide the basis for the development of novel anti-epileptic drugs.

Summary

The mammalian central nervous system is composed of many different types of nerve cells. These cells differ in the target that they contact, the signalling chemicals (neurotransmitters) they release, and the way in which they are able to fire electrical action potentials that trigger release of their neurotransmitter(s). Abnormalities in any of these aspects of neuron function have the possibility to result in neurological disorders including, but not limited to, schizophrenia, depression and epilepsy. It is implicit, therefore, that in order to design better and more effective treatments for neurological disorders, the underlying causes need to be fully understood. Epilepsy is a case in point. Currently only about 70% of sufferers respond to drug treatment; the remaining 30% do not. Clearly additional drugs are required. However, before new drugs can be designed, novel target molecules need first to be identified. Only after identification can drugs be designed to interact with and effect such molecules. To this end, we are using the fruitfly, Drosophila melanogaster, because it is very amenable to genetic analysis, its genome has been sequenced, and because it provides a simple, yet comparable, model of the human nervous system. It is of significance for this project that a number of mutations have been identified that make flies susceptible to epileptic-like seizures. Seizures in the fly are remarkably similar to seizures in humans. Using the genetic tractability of the fly, we hope to identify novel genes that, when mis-regulated, ameliorate seizures and, by doing so, identify new avenues for human drug design.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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