The research of my group focuses on understanding the signalling events that are triggered by activity, and their impact on neuronal survival and death.
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.
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 (such as Foetal Alcohol Syndrome).
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.
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.
Wyllie, D. J. A., M. R. Livesey and G. E. Hardingham (2013). "Influence of GluN2 subunit identity on NMDA receptor function." Neuropharmacology 74: 4-17.
McKay, S., C. P. Bengtson, H. Bading, D. J. A. Wyllie and G. E. Hardingham (2013) Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure. Neuropharmacology 74: 119-125.
Bilican, B., A. Serio, S.J. Barmad, A.L. Nishimura, G,J. Sullivan, M, Carrasco, H.P. Phatnani, C.A. Puddifoot, D. Story, J. Fletcher, I.-H. Park, B.A. Friedman, G.Q. Daley, D.J.A. Wyllie, G.E. Hardingham, I. Wilmut, S. Finkbeiner, T. Maniatis, C.E. Shaw and S. Chandrana, (2012). "Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability." Proceedings of the National Academy of Sciences of the United States of America 109(15): 5803-5808.
Martel, M. A., T.J. Ryan, K.F. Bell, J.H. Fowler, A. McMahon, B. Al-Mubarak, N.H. Komiyama, K.Horsburgh, P.C. Kind, S.G. Grant, D.J. Wyllie and G.E. Hardingham. (2012). The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults. Neuron 74(3): 543-556.
McMahon AC, Barnett MW, O’Leary TS, Stoney PN, Collins MO, Papadia S, Choudhary JS, Komiyama NH, Grant SGN, Hardingham GE, Wyllie DJA and Kind PC (2012) Activity-dependent alternative promoter usage and alternative splicing enable SynGAP isoforms to exert opposing effects on synaptic strength. Nature Communications. 3.
Puddifoot, C., M.A. Martel, F.X. Soriano, A. Camacho, A. Vidal-Puig, D.J.A. Wyllie and G.E. Hardingham. (2012). PGC-1 alpha Negatively Regulates Extrasynaptic NMDAR Activity and Excitotoxicity. Journal of Neuroscience 32(20): 6995-7000.
Hardingham GE and Bading H (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nature Reviews Neuroscience 11, No. 10.
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.
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
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, and 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, and 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.
This article was published on Feb 5, 2014