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John Garthwaite

Neural Signalling
John Garthwaite


Tel: 020 7679 6694
Email: john.garthwaite@ucl.ac.uk 

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. 

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.

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.

Neurodegeneration

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.

Academic Career

  • 1996-present Professor of Experimental Neuroscience, Wolfson Institute for Biomedical Research, UCL
  • 1992-1995 Head of Neuroscience Research, Wellcome Research Laboratories, Beckenham, Kent
  • 1980-1992 Lecturer-Professor, Department of Physiology, University of Liverpool
  • 1976-1980 Research/Scientific Officer, MRC Developmental Neurobiology Unit, Carshalton and London
  • 1973-1976 PhD (Pharmacology), University of London
  • 1972 BSc Biochemistry (Medical), University of Surrey

Publications

Bhargava Y, Hampden-Smith K, Chachlaki K, Wood KC, Vernon J, Allerston CK, Batchelor AM and Garthwaite J (2013) Improved genetically-encoded, FlincG-type fluorescent biosensors for neural cGMP imaging. Front. Mol. Neurosci., 6: 26.

Wood KC, Batchelor AM, Bartus K, Harris KL, Garthwaite G, Vernon J, Garthwaite J. (2011)Picomolar nitric oxide signals from central neurons recorded using ultrasensitive detector cells. J Biol Chem. 286(50):43172-81.

Batchelor AM, Bartus K, Reynell C, Constantinou S, Halvey EJ, Held KF, Dostmann WR, Vernon J, Garthwaite J.(2010) Exquisite sensitivity to subsecond, picomolar nitric oxide transients conferred on cells by guanylyl cyclase-coupled receptors. Proc Natl Acad Sci U S A. 107(51):22060-5.

Halvey EJ, Vernon J, Roy B, Garthwaite J. (2009) Mechanisms of activity-dependent plasticity in cellular nitric oxide-cGMP signaling. J Biol Chem. 284(38):25630-41.

Roy B, Halvey EJ and Garthwaite J (2008) An enzyme-linked receptor mechanism for nitric oxide-activated guanylyl cyclase. J. Biol. Chem. 283: 18841-18851

Garthwaite, J. (2008) Concepts of neural nitric oxide-mediated transmission. Eur. J. Neurosci. 27: 2783-2802.

Further publication information can be viewed at https://iris.ucl.ac.uk/iris/browse/profile?upi=JGART99