The research of my group focuses on signalling events within and between neurons and glia, and how these interactions shape brain development and homeostasis as well as drive pathological cascades.
The overarching aim is to understand how signaling between and within different components of the neuroglial system maintains brain homeostasis, and how this goes awry in disease.
There is a deficit in our fundamental understanding of how neurons and glia control each others properties both basally, in response to physiological stimuli, and under pathological conditions. By exploiting new approaches that allow us to profile multiple cell types simultaneously we will uncover novel mechanisms by which inter- and intra-cellular signals integrate to achieve homeostasis in the neuroglial unit, and uncover mechanisms of non cell-autonomous neurotoxicity in neurodegeneration.
Physiological patterns of synaptic activity are strongly neuroprotective, the basis for which is incompletely understood. Synaptic activity induces signalling pathways which activate new gene expression as well as triggering the post-translational modification of existing proteins.
It is becoming clear that neuronal activity triggers adaptive, protective responses to tune a neuron's metabolic, redox buffering and other homeostatic properties to reflect the needs of an active neuron.
Qiu J, McQueen J, Bilican B, Dando O, Hagh G, Cezard T, Burr K, Patani R, Rajan R, Sheppard O, Kind PC, Simpson I, Tybulewicz VLJ, Wyllie DJA, Gharbi K, Fisher EMC, Chandran S and Hardingham GE (2016). Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons. eLife. Oct 1;5. doi: 10.7554/eLife.20337.
Hardingham, GE and Do, KQ. Early-life oxidative stress and NMDAR hypofunction as an interlinked pathological hub in schizophrenia (2016). Nature Reviews Neuroscience 17:125-34.
Baxter. PS, Bell, KFS, Hasel, P, Kaindl, AM Fricker, M, Thomson, D, Cregan, SP, Gillingwater, TH and Hardingham, GE (2015). Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system in the developing forebrain. Nature Communications Apr 9;6:6761.
Bell KFS and Hardingham GE (2011) The influence of synaptic activity on neuronal health. Current Opinion in Neurobiology Apr;21(2):299-305.
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. 2623-35.
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.
Astrocytes and neurons are metabolically coupled at to achieve brain homeostasis. We are interested in how this homeostasis is achieved, and how the homeostatic capacity of astrocytes is controlled to support the demands of neurons. We study pathways that control neurotransmitter uptake, antioxidant support, and bioenergetic balance in the brain.
Hasel P, Dando O, Jiwaji Z, Todd A, Heron S, Márkus NM, Baxter P, McQueen J, Hampton D, McKay S, Tiwari S, Torvell M, Chandran S, Wyllie DJA, Simpson TI, and Hardingham GE (2017). Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolic function. Nature Communications (in press).
Bell, KFS, Al-Mubarak, B, Martel, MA, McKay, S, Wheelan, N, Hasel, P, Márkus, NM, Baxter, P, Deighton, RF , Serio, A Bilican, B, Chowdhry, S, Meakin, PJ, Ashford, MLJ, Wyllie, DJA, Scannevin, RH, Chandran, S Hayes, JD and Hardingham, GE (2015). Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2. Nature Communications May 13;6:7066.
Deighton RF, Márkus NM, Al-Mubarak, Bell KFS, Papadia S, Meakin PJ, Chowdhry S, Hayes JD, and Hardingham GE (2014). Nrf2 target genes can be controlled by neuronal activity in the absence of Nrf2 and astrocytes. PNAS May 6;111(18):E1818-20.
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. PNAS 108, E1-2.
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, spatial calcium dynamics and mitochondrial calcium overload in influencing survival/death following NMDAR activation.
Qiu, J., Tan, Y., Hagenston, A.M., Martel, M., Kneisel, N., Skehel, P.A., Wyllie, D.J.A, Bading, H., and Hardingham, G. E. (2013). Mitochondrial uniporter Mcu controls excitotoxic neuronal cell death and is transcriptionally repressed by neuroprotective nuclear Ca2+ signals. Nature Communications 4:2034.
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.
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.