Dr Giles Hardingham

Dr Giles Hardingham BSc PhD 
Principal Investigator
Royal Society University Research Fellow
Centre for Neuroscience Research
Hugh Robson Building
George Square
Edinburgh, EH8 9XD

Telephone: 44 (0)131 650 7961 (office);  7960 (lab)
Fax: 44 (0)131 650 6527
Email: Giles.Hardingham@ed.ac.uk
     
Click here for a printable one page CV

Biographical Profile


Dr. Hardingham received his degree in Biochemistry from the University of Cambridge.   He went on to do a PhD with Professor Hilmar Bading at the MRC Laboratory of Molecular Biology, Cambridge on spatial aspects of Ca2 signalling in excitable cell lines.   In 1998 he obtained an MRC Research Fellowship to continue working at the LMB on activity-dependent gene expression in neurons.   He was also a Fellow of Clare College, Cambridge and Tutor in Molecular Biology.   In 2002 he moved to the University of Edinburgh to investigate aspects of activity-dependent gene expression and their impact on neuronal fate and function.   He is a Royal Society Research  Fellow and Reader.

Research Overview

Research: Pro-survival and pro-death signalling from the NMDA receptor
In central neurons, Ca2 entry through the NMDA-type glutamate receptor (NMDAR) is a major source of synaptically-evoked Ca2 transients and directly affects neuronal survival/death:  while too much NMDAR activity is harmful, so is too little (Hardingham and Bading, 2003;  Papadia and Hardingham, 2007).   Understanding the mechanisms behind this dichotomous signalling is an area of molecular neuroscience with direct clinical implications.   The research of my group focuses on understanding the signalling events that are triggered by NMDAR activity, and their impact on neuronal survival and death, and comprise three main themes:

Theme 1: Investigation into anti-apoptotic signalling afforded by synaptic NMDAR activity: Physiological patterns of synaptic NMDAR activity are strongly neuroprotective, the basis for which is unclear. Synaptic NMDAR activity induces signalling pathways which activate new gene expression as well as triggering the post-translational modification of existing proteins. We aim to understand the molecular events that underlie activity-dependent neuroprotection, including the role of gene expression changes. An understanding of the brain's natural "neuroprotective" mechanisms is important, since malfunction of these mechanisms may contribute to neurodegeneration in a variety of debilitating brain disorders (Alzheimer's, ALS, Huntington's, Parkinson's), and also neurodevelopmental disorders associated with NMDA receptor inhibition (e.g. Foetal Alcohol Syndrome).

Theme 2: Investigation into the regulation of antioxidant defences by synaptic NMDAR activity: Intrinsic antioxidant defences are important for neuronal longevity. However, little is known about whether they are subject to dynamic regulation, or are a fixed function of neuronal type/age. This is an important question: any regulation could influence biological ageing, or progression of neurodegenerative disorders associated with oxidative damage. We are studying the influence of synaptic NMDAR activity on antioxidant enzymic systems and how it influences the vulnerability of neurons to oxidative insults.

Theme 3: Understanding the differences between protecting and toxic episodes of NMDAR activity: This theme is aimed at understanding what parameters determine whether an episode of NMDAR activity promotes neuroprotection, or cell death, other than simply the magnitude of Ca2 influx. We are examining the relative importance of NR2 subunit composition, PDZ protein interactions, synaptic vs. extrasynaptic location and spatial calcium dynamics in influencing survival/death following NMDAR activation.

We employ a large array of techniques to realise our research aims. Gene regulation programmes are analysed by expression analysis (Genechip), RT-PCR and chromatin-IP. The role of individual genes is probed by siRNA and over-expression studies, while NMDAR signalling is studied via an array of electrophysiological, live-cell imaging techniques, and second messenger assays. We collaborate with colleagues within the University (David Wyllie, Karen Horsburgh, Donald Salter, Peter Kind) and elsewhere (including Chrysanthy Ikonomidou (Dresden), Aviva Tolkovsky (Cambridge) and Angela Kaindl (Berlin)).

School of Biomedical Sciences Research Briefing

Collaborators

Prof. Hilmar Bading: University of Heidelberg
Prof. Martin Privalsky: UC Davis
Prof. Hrissanthi Ikonomidou: University of Dresden
Dr David Wyllie: Centre for Neuroscience Research
Dr Donald Salter: Dept of Pathology, University of Edinburgh
Dr. Grahame Mckenzie: Lorantis

Current Grants

Royal Society: www.royalsoc.ac.uk
The Wellcome Trust: www.wellcome.ac.uk
The European Commission: www.cordis.lu
BBSRC: http://www.bbsrc.ac.uk/
Arthritis and Rheumatism Council: www.arc.org.uk

Select Recent Publications

Soriano, F. X. , Martel, M-A., Papadia, S., Leveille, F., Clarke, P.G.H., Vaslin, A., Forder, J., Aarts, M., Wyllie, D., Tymianski, M. and Hardingham, G.E (2008). Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. Journal of Neuroscience 28, 10696-10710.

Papadia S, Soriano F, Léveillé F, Martel M, Dakin2 K, Hansen H, Kaindl A, Sifringer M, Fowler J, Stefovska V, Mckenzie G, Craigon M, Corriveau R, Ghazal P, Horsburgh H, Yankner B, Wyllie D, Ikonomidou C, Hardingham GE (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defences. Nature Neuroscience 11:476-487.

Soriano FX, Papadia S, Hofmann F, Hardingham NR, Bading H, Hardingham GE (2006) Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability. Journal of Neuroscience 26:4509-4518.

Papadia S, Stevenson P, Hardingham NR, Bading H, and Hardingham GE (2005) Nuclear Ca2 and the CREB family mediate a late-phase of activity-dependent neuroprotection. Journal of Neuroscience 25: 4279-87

Hardingham GE and Bading H (2003) "The Yin and Yang of NMDA receptor signalling". Trends in Neurosciences 26: 81-89

Hardingham GE, Fukunaga Y, and Bading H (2002) "Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways". Nature Neuroscience 5: 405-414

Hardingham GE, Arnold F, and Bading H (2001) "Nuclear Ca2 signaling controls CREB-mediated gene expression triggered by synaptic activity". Nature Neuroscience 4: 261-267

Key Earlier Publications

Hardingham GE, Arnold F, and Bading H (2001) "Ca2 microdomain near NMDA receptors: on-switch of ERK-dependent synapse-to-nucleus communication". Nature Neuroscience 4: 565-566
     
Hardingham GE, Chawla S, Cruzalegui FH, and Bading H (1999) "Control of recruitment and activation of CBP determines gene regulation by NMDA receptors and L-type Ca2 channels" Neuron 22: 789-798

Chawla S1, Hardingham GE1, Quinn D, and Bading H (1998) "CBP: A signal-regulated transcriptional coactivator controlled by nuclear Ca2 and CaM kinase IV" Science 281: 1505-1509 (1Joint first authors)

Hardingham GE, Chawla S, Johnson CM, and Bading H (1997) “Distinct functions of nuclear and cytoplasmic Ca2 in the control of gene expression” Nature 385: 260-265

For more papers by Dr G E Hardingham click here