Centre for Integrative Physiology
University of Edinburgh
Hugh Robson Building
George Square
EH8 9XD - Edinburgh
United Kingdom

+44 (0)131 650 7961 (office); 7960 (lab)
+44 (0) 131 650 6576
giles.hardingham@ed.ac.uk

Job opportunities

In neurons, Ca2+ entry through the NMDA 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. My group is interested in understanding the mechanisms behind this dichotomous signalling. A significant part of our work concerns the mechanisms and consequences of signalling to gene expression, since this is an important route by which pro-survival changes to neurons are effected.  Specifically, our work comprises 3 themes, each supported by project grants:
1.Identification of the genes induced or suppressed by synaptic NMDAR activity which are responsible for activity-dependent neuroprotection.
2. Investigation of a novel mechanism we uncovered by which synaptic NMDAR activity can de-repress genes by triggering the nuclear export of broad specificity transcriptional corepressors.
3. Investigating the differences in Ca2+ signalling to pro-survival and pro-death events, and using this knowledge to assess ways of interfering with pro-death NMDAR signalling without affecting the important pro-survival signalling cassettes.

Gupta, K., Patani, R., Baxter, P., Hardingham. G.E.* and Chandran, S.*. Human astrocytes mediate non-cell autonomous neuroprotection through endogenous and drug-induced mechanisms. Cell Death & Differentiation (in press).

S McKay, NH Griffiths, PA Butters, EB Thubron, GE Hardingham and DJA Wyllie. NMDA receptor subunit-selective antagonism by N-(cyclohexylmethyl)-2-({5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio)acetamide is glycine-dependent. British Journal of Pharmacology. Oct 24. doi: 10.1111/j.1476-5381.2011.01748.x. [Epub ahead of print]

R. Patani, A.J. Hollins, T.M. Wishart, C.A. Puddifoot, S. Álvarez, A.R. de Lera, D.J.A. Wyllie, D.A.S. Compston, R.A. Pedersen, T.H. Gillingwater, G.E. Hardingham, N.D. Allen, S. Chandran (2011). Retinoid independent generation of functional motor neurons from human embryonic stem cells reveals a medial columnar groundstate. Nature Communications Mar;2:214.

Bell KFS, Mubarak B, Fowler J, Baxter PS, Gupta K, Tsujita T Chowdhry S, Horsburgh K, Hayes JD and Hardingham GE (2011) Mild oxidative stress activates Nrf2 in astrocytes which contributes to neuroprotective ischemic preconditioning. Proc. Natl. Acad. Sci. USA 108, E1-2.

Baxter, PS, Martel, MA, McMahon, A, Kind, PC, and Hardingham, GE (2011). Pituitary adenylate cyclase-activating peptide (PACAP) induces long-lasting neuroprotection through the induction of activity-dependent signaling via the cAMP response element-binding protein (CREB) -regulated transcription coactivator 1 (CRTC1). Journal of Neurochemistry Aug;118(3):365-78.

Bell KFS and Hardingham GE (2011) The influence of synaptic activity on neuronal health. Current Opinion in Neurobiology Apr;21(2):299-305.

Soriano, FX and Hardingham, GE (2011). In cortical neurons HDAC3 deacetylase activity suppresses RD4-dependent SMRT export. PLoS ONE 6(6):e21056. Epub 2011 Jun 9.

Bell KFS, Fowler J, Mubarak B, Horsburgh K and Hardingham GE (2011). "Activation of Nrf2-regulated glutathione pathway genes by ischemic preconditioning". Oxidative Medicine and Cellular Longevity 2011:689524. Epub 2011 Jun 28

Hardingham GE  and Lipton SA (2011). Regulation of neuronal oxidative and nitrosative stress by endogenous protective pathways and disease processes. Antioxidants and Redox Signalling Apr 15;14(8):1421-4.

*Hardingham GE  and Bading H (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Reviews Neuroscience 11, 682-696.

Soriano, FX, Leveille, F, Bell, KS, Privalsky, M and Hardingham, GE (2011). Neuronal activity controls the antagonistic balance between PGC1a and SMRT in regulating antioxidant defences. Antioxidants and Redox Signalling 14(8):1425-36.

Fricker, M, Papadia, S, Hardingham, GE, and Tolkovsky, AM (2010). Implication of p73 in the p53-independent pathway of Puma-induction and Puma-dependent apoptosis in primary cortical neurons. Journal of Neurochemistry 114(3):772-83.

Bell KS and Hardingham GE (2011). CNS peroxiredoxins and their regulation in health and disease.  Antioxidants and Redox Signalling Apr 15;14(8):1467-77..

*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. The Journal of Neuroscience 30. 263-265.

Hardingham, G.E., Patani, R., Baxter, P. and Chandran S (2010). Human embryonic stem cell-derived neurons as a tool for studying neuroprotection and neurodegeneration. Molecular Neurobiology  42, 97-102. Special Issue: “Mechanisms of cell death”.

Hardingham, G.E. (2009). Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem Soc Trans (Colworth Medal Review). Dec;37(Pt 6):1147-60

Patani, R., Puddifoot, C., Wyllie, D.J.A, Hardingham, G.E., Compston, D.A.S,  Allen, N.D., Chandran, S. (2009). Activin/Nodal inhibition alone accelerates highly efficient neural conversion from human embryonic stem cells and imposes a caudal positional identity. PLoS One. Oct 6;4(10):e7327.

Mubarak B, Soriano F, Papadia S,  and Hardingham, G.E. (2009). FOXO1 expression is supressed by synaptic activity via FOXO export: FOXO1 is a FOXO target gene. Channels 3(4):233-8.

Soriano, F.X., Papadia, S.,  Bell, F.S. and Hardingham, G.E. (2009). Role of histone acetylation in the activity-dependent regulation of sulfiredoxin and sestrin 2. Epigenetics 4, 10-17.

Leveille, F. and Hardingham G.E. (2009). Excitotoxic insults promote peroxiredoxin hyperoxidation. Oxidative Medicine and Cellular Longevity 2, 98-101.

Martel, M., Wyllie, D., and Hardingham, G.E. (2009) In developing hippocampal neurons, NR2B-containing NMDA receptors can mediate signalling to neuronal survival and synaptic potentiation, as well as neuronal death. Neuroscience 158,  334-343.

Martel MA, Soriano FX, Rickman C, Papadia S, Baxter P, Duncan R, Wyllie DJ. and Hardingham, G.E (2009). Inhibiting pro-death NMDA receptor signaling dependent on the NR2 PDZ ligand may not affect synaptic function or synaptic NMDA receptorsignaling to gene expression. Channels 3, 12-15.

Soriano F.X., Baxter P., Murray L.M., Sporn M.B., Gillingwater T.H. and Hardingham G.E. (2009). Transcriptional regulation of the AP-1 and Nrf2 target gene sulfiredoxin. Molecules and Cells 27,1-4.

Wahl, A., Buchthal, B., Rode, F., Bomholt, S., Freitag, E., Hardingham, G.E., Rønn, L.C., Bading, H. (2009). Hypoxic/ischemic conditions induce expression of the putative pro-death gene Clca1 via activation of extrasynaptic NMDA receptors. Neuroscience 334-352

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

See also News & Views article by Stuart A. Lipton

Soriano, F. X. , Leveille, F., Papadia, S., Higgins, L., Varley, J., Baxter, P., Hayes, J.D., and Hardingham, G.E (2008). Induction of sulfiredoxin expression and reduction of peroxiredoxin hyperoxidation by the neuroprotective Nrf2 activator 3H-1,2-dithiole-3-thione. Journal of Neurochemistry 107, 533-543.

*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. The Journal of Neuroscience 28, 10696-10710

Ramage , L., Martel, M., Hardingham, G.E., Salter, D.M. (2008). NMDA receptor expression and activity in osteoarthritic human articular chondrocytes. Osteoarthritis and Cartilage 16, 1576-1584

Soriano F.X. and Hardingham, G.E. (2007). Compartmentalized NMDA receptor signalling to survival and death. Journal of Physiology 584, 381-387.

Hardingham, N., Hardingham, G.E., Fox, K., Jack, J (2007) Pre-synaptic efficacy directs normalization of synaptic strength following paired activity. Journal of Neurophysiology 97, 2965.

Papadia, S. and Hardingham, G.E (2007). The dichotomy of NMDA receptor signalling. The Neuroscientist 13, 572-579.

Soriano, F. X., Papadia, S., Hofmann, F., Hardingham, N., Bading, H., Hardingham, G. E. (2006):Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability..Journal of Neuroscience: 26, 4509-18

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

Hardingham, G.E., Hilmar Bading (2003):The Yin and Yang of NMDA receptor signalling..Trends in Neurosciences: 26, 81-89. Refereed review

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

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

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