My overarching interests centre on how Ca2+ signals control gene expression in neurons, and how this in turn controls both neuronal survival and death. One major principle that I established was that Ca2+ signals with different spatial properties can trigger distinct transcriptional responses in neurons. I demonstrated in papers published in Nature and Nature Neuroscience ´97-01 that Ca2+ can act in the nucleus, the cytoplasm, and in submembranous regions to trigger qualitatively distinct patterns of gene expression. I found a key role for nuclear Ca2+ in controlling activity-dependent induction of a transcription factor called CREB and subsequently implicated both CREB and nuclear Ca2+ in the neuroprotective effects of synaptic activity. Another contribution to the field of Ca2+mediated transcriptional control was to show that transcriptional coactivators and corepressors can be targets for neuronal Ca2+-activated signal pathways, and not just the transcription factors themselves. I was a joint 1st author on the first study (in Science ´99) to show that a transcriptional coactivator (CBP) could be controlled by Ca2+.
Much of my work on Ca2+ signalling concerns the NMDA receptor (NMDAR), through which Ca2+ flows during normal glutamatergic synaptic transmission. As described in my recent article in Nature Reviews Neuroscience ´10, the NMDAR has a unique place in neuronal physiology: on the one hand, physiological NMDAR activity mediates synaptic plasticity and promotes neuronal survival during development. On the other hand, NMDAR excitotoxicity is a key mediator of neuronal loss following stroke, and may be linked to neurodegenerative diseases such as Huntington´s. I have made contributions in understanding the basis of this dichotomous signalling. Reported in a series of papers in Nature Neuroscience and J. Neurosci ´02-´08, I discovered that the nature of NMDAR signalling depends on receptor location. While survival-promoting signals are triggered by synaptic NMDARs, a dominant cell death-promoting signal emanates from extrasynaptic NMDARs. More recently we have established a role for the recently discovered mitochondrial calcium uniporter in excitotoxicity (Nat. Comm 2013).
I have further uncovered molecular mechanisms underlying synaptic NMDAR-dependent neuroprotection, recently describing in Nature Neuroscience and J. Neurosci t ´05-´10 he complex series of transcriptional changes that enable neurons to combat apoptotic and oxidative insults. I found that intrinsic antioxidant defences are subject to control by synaptic (but not extrasynaptic) NMDAR activity, based on a coordinated program of gene expression centred on the thioredoxin enzymic system. Very recently I have begun working on understanding how neuronal vulnerability to oxidative stress can be influenced by adaptive neuroprotective responses from nearby astrocytes. For example, I characterized a transcription-dependent neuroprotective pathway initiated in astrocytes and relevant to neuroprotective ischemic preconditioning, published in PNAS ´11. We also continue to investigate the key differences between protective and toxic episodes of NMDAR activity, particularly pro-death events mediated by the C-termini of specific NMDAR subunits, such as those described in J. Neurosci ´08 as well as more recent work published in Neuron ´12.
Qiu J., Tan Y., Hagenston AM., Martel M., Kneisel N., Skehel PA., Wyllie DJA, Bading H., Hardingham GE. (2013) Mitochondrial uniporter Mcu controls excitotoxic neuronal cell death and is transcriptionally repressed by neuroprotective nuclear Ca2+ signals. Nat. Commun., 4 : 2034.
Martel M., Ryan TJ., Bell KFS., Fowler JH., McMahon A., Komiyama NH., Horsburgh K., Kind PC., Grant SGN., Wyllie DJA, Hardingham GE. (2012) The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron., 74 (3) : 543-56.
Puddifoot C. , Martel M., Soriano FX., Camacho A., Vidal-Puig A.,Wyllie DJ., Hardingham GE. (2012) PGC-1α negatively regulates extrasynaptic NMDAR activity and excitotoxicity. J Neurosci., 32 (20) : 6995-7000.
Léveillé F., Papadia S., Fricker M., Bell KF., Soriano FX., Martel MA., Puddifoot C., Habel M., Wyllie DJ., Ikonomidou C., Tolkovsky AM., Hardingham GE. (2010) Suppression of the intrinsic apoptosis pathway by synaptic activity. J. Neurosci., 30 (7) : 2623-35.
Papadia S., Soriano FX., Leveillé F., Martel M., Dakin K., Hansen H., Kaindl A., Sifringer M., Fowler J., Stefovska V., Mckenzie GM., Craigon M., Corriveau R., Ghazal P., Horsburgh K., Yankner B., Wyllie D., Ikonomidou C., Hardingham GE. (2008) Synaptic NMDA receptor activity boosts intrinsic antioxidant defences. Nat. Neurosci., 11 (4) : 476-87.
2011 International Society for Neurochemistry Young Scientist Award
2010 MRC Senior Non-Clinical Research Fellowship (to Oct 2015)
2009 Colworth Medal awarded by the UK Biochemical Society for “outstanding research by a young biochemist (under 35)
2009 University of Edinburgh Chancellor’s Rising Star Award. Presented by HRH Prince Philip, Chancellor
2009 Finalist Eppendorf European Investigator Award. Presented with Eppendorf
2008 Elected as an EMBO Young Investigator. One of 12 chosen Europe-wide.
2006 Royal Society Research Fellowship renewed and merit award
2004 Invited participant at the Roche Symposium for Leading Bioscientists of the Next Decade
2002 Royal Society University Research Fellowship
2000 Rolleston Memorial Prize for research in the biological sciences carried out in Oxford or Cambridge
1999 Amersham Pharmacia Biotech and Science Prize for Young Scientists(European Section).
1998 MRC Post-doctoral Research Fellowship (3 years)
1998 Elected a Fellow of Clare College, Cambridge
1998 MRC Max Perutz Prize for outstanding research (PhD students)