Distribution of RNA coding for different subunits of receptors for nitric oxide in the rat brain. Black, low density; white, high density.
Professor John Garthwaite
|Tel: +44 (0)20 7679 6694|
Professor John Garthwaite
Our interest is in understanding how cells in the brain carry out their main task, which is to communicate with one another and store information. We also aim to understand how abnormalities in communication can arise, because these are important in brain disorders such as epilepsy and chronic pain, as well as for the injury and death of brain cells that occurs acutely in conditions such as stroke, or more chronically in Alzheimer's and Parkinson's and other diseases.
Nitric oxide signalling
One of the most curious ways in which brain cells communicate with each other is through the very simple but potentially toxic molecule, nitric oxide (NO). Almost all brain regions are able to make NO and, accordingly, it subserves many different functions, including memory formation, vision, feeding and drinking, sexual behaviour and the regulation of blood flow. Too much NO, however, can cause brain cells to die and hence the molecule is suspected of participating in a range neurodegenerative disorders. We are trying to understand how NO functions at the cellular level.
|This culture has been stained to show only the nerve cells that make nitric oxide. These represent only 1-2% of the total, but a dense network of their fibres is observed, paralleling what is seen in the intact brain. Though small in number, these cells may make toxic quantities of nitric oxide under pathological conditions, causing widespread cell death.|
Molecular characterisation of nitric oxide receptors
The best recognised NO receptors are a family of proteins that, on binding the molecule, synthesise the second messenger cyclic GMP which then leads to rapid or longer-term modifications to the way that synapses operate. We are investigating the diversity of receptors expressed in the brain, their distribution, and the dynamics of NO signal transduction through the different receptors.
Nitric oxide inactivation
In order to function as a messenger, NO needs to be inactivated. We have discovered that there is such a mechanism in the brain and that it serves to shape NO concentrations for physiological signalling while stopping NO rising to toxic amounts. We are currently characterising the process in terms of its molecular identity and underlying biochemical mechanism.
Synaptic transmission and plasticity
Short- and long-term adjustments are continually being made to the way that brain synapses operate. These changes contribute to learning and memory formation but are also likely to have relevance to the altered brain function in neurological disorders. Hence, a major goal is to unravel the mechanisms giving rise to the plasticity. We are studying how neurotransmitters act to modify ion channel function and thereby shape synaptic signals, and how NO brings about acute and longer-term changes in neuronal function.
|Electrical events in nerve cells triggered by the release of neurotransmitter. The larger response (yellow) appears after a brief period of intense activity and such changes, which can persist for hours or days, are considered to be cellular correlates of learning and memory formation.|
We are exploring the cellular mechanisms underlying acute and chronic damage to the brain, with particular emphasis on the roles of glutamate, NO and voltage-dependent sodium channels. To do so, several models have been developed, ranging from acutely isolated optic nerves to brain slices that can be kept alive for long periods (up to months) in slice culture.
Nitric oxide-induced cell death in brain slices kept in long-term
tissue culture. In this model, nitric oxide is applied to slices of
hippocampus, a brain region vulnerable to damage in acute and chronic
neurodegenerative disorders. Damage is not seen early on (top) but later
a progressive neurodegeneration sets in that requires about 3 days for
completion (bottom). The colours signify different degrees of cell
death, red being the maximum.
- Garthwaite, J. (2005) Dynamics of cellular NO-cGMP signalling. Front. Biosci. 10: 1868-1880.
- Riddall, D., Leach, M.J. and Garthwaite J. (2005) A novel drug binding site on voltage-gated sodium channels in rat brain. Mol. Pharmacol. Epub October 11.
- Garthwaite, G., Batchelor, A.M., Goodwin, D.A., Hewson, A.K., Leeming, K, Ahmed, Z., Cuzner, M.L. and Garthwaite, J. (2005) Pathological implications of iNOS expression in central white matter: an ex vivo study of optic nerves from rats with experimental allergic encephalomyelitis. Eur. J. Neurosci. 21: 2127-2135.