Approximately 50 million people worldwide suffer from epilepsy. Chronic temporal lobe epilepsy (TLE) is one of the most prevalent forms of the syndrome. Currently this disorder is predominantly untreatable with medicines. It often occurs after a traumatic head injury (as, for example, that caused by a car accident) or fits induced by high fever. There is a delay (the so-called ‘latent period’) between the precipitating insult and the occurrence of spontaneous fits (seizures; defined as the onset of chronic TLE). It is during the latent period that changes in the brain leading to spontaneous fits occur. To obtain better treatment for chronic TLE, it is important to understand these changes. Ion channels are specialized proteins present in the membranes of brain nerve cells and are important for determining their function. Using models that replicate many if the features of the the human condition, I have recently shown that during the latent period, a particular ion channel, the h-channel, is persistently reduced in number in the cortex (an area of the brain where seizures are generated). I now wish to investigate more about the role of this channel in seizure generation. I also wish to understand more about how the expression of this channel is regulated in neurons. To do this, I am using a variety of state-of-the art techniques including recording electrical currents produced by activation of ion channels from single, genetically modified cortical nerve cells. The possible ramifications of this research are manifold, including a better understanding the mechanisms underlying TLE and the identification of novel treatment strategies.

There are many cells in the brain (109), which are wired to form specialized circuits. These circuits have many functions ranging from; perception, movement and memory. How the circuits perform their tasks is largely due to the type of receptors they posses, their morphological structure and who they are wired with. This complex wiring of neurones makes the brain the most complex organ however; the way it works can be simplified into two opposing forces; excitation and inhibition. Neurones which work via chemical synapses are excited by excitatory pyramidal cells using neurotransmitter glutamate and are inhibited by inhibitory interneurones releasing the neurotransmitter, GABA that acts on GABA receptors. Under or over activity of these 2 opposing forces have been implicated in neurodegenerative (e.g. epilepsy and Parkinson?s disease) and psychiatric diseases (e.g. anxiety and schizophrenia). The proposed research is to provide a better understanding of how the homeostatic balance of inhibition and excitation is achieved. 80% of cells in cortical regions consist of the pyramidal cell family while inhibitory interneurones consist of 6-7% of cells in cortical regions. Interneurones fall into different sub families, which are diverse in their morphology, neurochemistry, electrophysiological properties and the type of GABA receptors they posses. The interneurones make synapses with pyramidal cells and other interneurones to regulate and fine tune pyramidal cell activity, thus preventing over excitability of the network. This study is very important since not only will it provide valuable information on interneurone physiology, pharmacology and morphology but will also provide insight on neuronal subtypes which may be selectively affected in a particular disease states. The outcome of this research has direct relevance to human neuropathology, since it will allow us to design drugs to target specific pathways in the brain to treat neurological disorders, including depression and anxiety, which impact significantly on UK citizens, i.e. 1 in 4 adults may experience a mental health problem in any given year. Depression alone is thought to be the second most costly illness worldwide (Murray and Lopez, 1996) by year 2020, representing the biggest global economic health burden after heart disease. The treatment for such disorders include benzodiazepines, barbiturates, which act through GABAA neurotransmitter receptors, making the GABAA receptor a prime target for the development of new drugs and improved selectivity of existing ones.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Meningitis and sepsis remain devastating diseases, particularly in the young. If patients survive, there are usually serious consequences that include mental retardation, seizures, cerebral palsy and hearing loss. Antibiotic therapy may not always be effective because the infection progresses very rapidly and antibiotic resistant bacteria are now more commonly found. There is widespread recognition that new approaches to the treatment of the disease are urgently needed. These serious infections in the newborn infant and in older children are caused by a relatively small number of bacterial types and they are almost all protected from the effects of the patient?s immune system by a coat, or capsule, comprising linked sugar molecules. There is ample evidence that the capsule is essential for the survival of the bacteria within the tissues of the patient, as without it they are no longer able to protect themselves from immune attack. We are looking for ways to rapidly remove this protective layer as a novel way of treating the infection ? our approach, which we call phenotypic modification, does not rely on directly killing the bacteria in the way that most antibiotics do, but aims to convert them to a ?less fit? form that cannot survive in the body. We have found an enzyme, derived from a bacterial virus or ?bacteriophage?, which quickly and selectively strips the capsule from the bacterial surface and sensitises the pathogenic organisms to the body?s defences. We have used the enzyme to treat experimental infections in newborn rats and we find that injection of very small amounts of material can very effectively cure the animals of what is invariably a fatal infection. This is the first demonstration that we know of which shows that ?phenotypic modification? can work in whole animals. We now which to achieve a greater understanding of the nature of the infection in the animal model by studying the distribution of the pathogen in animal tissues and organs and we would also like to establish that the positive therapeutic outcome that we observe is really due to removal of the protective capsule at the site of infection. Finally, we propose to use ?microarray technology? to establish whether key rat gene products are involved in the determination of the therapeutic outcome.

The central nervous system is a complex, intricate network of nerve cells (neurones) whose primary function is to transmit and receive messages. This communication occurs at specialised sites of contact known as synapses. At these sites, an arriving nerve impulse causes the release of a chemical (neurotransmitter) from the presynaptic cell which then interacts with receptor molecules embedded in the cell membrane of a neighbouring postsynaptic neurone. Some types of these receptors (e.g. glycine and GABA-A receptors) possess specific ion-permeable channels. The opening of these channels in response to neurotransmitter alters the electrical state of the cell either transmitting or subtly altering the incoming nerve impulse. Neurotransmitters are then recovered from the synapse by transporters located in neighbouring glial cells or the corresponding presynaptic cell. The mechanisms that regulate synaptic transmission and nerve impulse activity are important in understanding normal and diseased states of the brain. Indeed, many drugs in use or under development act primarily via GABA or glycine receptors and their transporters. The therapeutic nature of these agents provides a compelling reason for further understanding the molecular details of the structure and function of these proteins. This proposal will benefit research in this area by enhancing our knowledge concerning transporters for GABA and glycine. In a recent study we were able to show that genetic defects in the glycine transporter GlyT2 were responsible for causing a rare illness called hyperekplexia. This affects newborn children and is characterised by noise or touch-induced seizures which result in breath-holding episodes. In some instances hyperekplexia can lead to brain damage or sudden infant death. Our major aims are: i) to study the consequences of GlyT2 mutations to reveal how these defects disable the transporter, and to investigate whether defects in a glycine transporter found on synaptic vesicles (VIAAT) or proteins that associate with GlyT2 can also cause hyperekplexia; ii) to determine whether genetic mutations in a second glycine transporter, GlyT1, is responsible for cases of a different childhood illness, glycine encephalopathy, which can lead to severe brain damage or death; iii) since defects in GABA receptors are found in some types of epilepsy, we will investigate whether mutations in GABA transporter genes also cause epilepsy. It is our hope that a detailed understanding of the genetic defects responsible for these illnesses will enable better diagnosis and treatment of affected individuals.