We study neurotransmitter action in central neurons to understand normal synaptic function and its dysfunction in models of neurodevelopmental and neurodegenerative diseases.
My long-standing research interest is in ligand-gated ion channels (LGICs) – specialized pore-forming membrane proteins that are activated by neurotransmitters during ‘fast’ chemical synaptic transmission. In particular my lab studies LGICs activated by L-glutamate – the major excitatory neurotransmitter in the mammalian brain.
Although glutamate activates several different classes of LGIC one in particular, the N-methyl-D-aspartate receptor (NMDAR) has been a major focus for our research. Through electrophysiological studies, my lab has contributed significantly to our understanding of the structure-function properties and physiological roles of the various subtypes of NMDARs.
NMDARs play pivotal roles in both normal and abnormal brain function. In early life for instance, they ensure that the correct wiring pattern is laid down in the developing brain. Furthermore, activation of NMDARs is required to learn certain tasks and store memories. However, both over- and under-activation of NMDARs can be deleterious for normal brain function. For example, during a stroke excessive activation of NMDARs contributes significantly to neuronal loss, while NMDAR dysfunction is thought to contribute to diseases such as Alzheimer’s, Parkinson’s and Schizophrenia. More recently it is now recognised that de novo mutations in the protein sequence of NMDARs can lead to intellectual disability. Directly related to our structure-function studies of NMDARs we use pre-clinical models of single gene causes of neurodevelopmental disorders (such as fragile X syndrome) to study the properties of altered synaptic function and to assess the extent to which pharmacological intervention can ameliorate the changes that are observed in such models.
A more recent focus of our research is the electrophysiological and functional characterization of defined neuronal and glial populations derived from human embryonic stem cells and induced pluripotent stem cells and specifically those from individuals suffering from neurodevelopmental and neurodegenerative diseases. Our work seeks to assess the electrophysiological profile of such neurons in order to further our understanding of these debilitating diseases.
Our overall aim is to develop an integrated approach to research that begins with the study of single protein molecules and synaptic function and extends, through collaboration with colleagues, to whole animal studies with an ultimate goal of the clinical study and treatment of disease.
We gratefully acknowledge present and past support for our research from the following:
Livesey MR, Magnani D, Cleary EM, James OT, Selvaraj BT, Burr K, Vasistha NA, Story D, Shaw CE, Kind PC, Hardingham GE, Wyllie DJA & Chandran S (2016). Maturation and electrophysiological properties of human pluripotent stem cell-derived oligodendrocytes. Stem Cells 34, 1040-1053. PMID: 26763608
Barnes SA, Wijetunge LS, Jackson AD, Katsanevaki D, Osterweil EK, Komiyama NH, Grant SGN, Bear MF, Nägerl UV, Kind PC & Wyllie DJA (2015). Convergence of hippocampal pathophysiology in Syngap+/- and Fmr1-/y mice. J Neurosci 35, 15073-15081. PMID: 26558778
Till SM, Asiminas A, Jackson AD, Katsanevaki D, Barnes SA, Osterweil EK, Bear MF, Chattarji S, Wood ER, Wyllie DJA & Kind PC (2015). Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS. Hum Mol Genet 24, 5977-5984. PMID: 26243794
Livesey MR, Magnani D, Hardingham GE, Chandran S & Wyllie DJA (2015). Functional properties of in vitro excitatory cortical neurones derived from human pluripotent stem cells. J Physiol 2015 Nov 26. doi: 10.1113/JP270660. [Epub ahead of print]
James OT, Livesey MR, Qiu J, Dando O, Bilican B, Haghi G, Rajan R, Burr K, Hardingham GE, Chandran S, Kind PC, Wyllie DJ. (2014) Ionotropic GABA and glycine receptor subunit composition in human pluripotent stem cell-derived excitatory cortical neurones. J Physiol. 592(Pt 19):4353-63.
Livesey MR, Bilican B, Qiu J, Rzechorzek NM, Haghi G, Burr K, Hardingham GE, Chandran S, Wyllie DJ. (2014) Maturation of AMPAR composition and the GABAAR reversal potential in hPSC-derived cortical neurons. J Neurosci. 34(11):4070-5.
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.
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.
Perkins EM, Clarkson YL, Sabatier N, Longhurst DM, Millward CP, Jack J, Toraiwa J, Watanabe M, Rothstein JD, Lyndon AR, Wyllie DJA, Dutia MB & Jackson M (2010). Loss of b-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci 30, 4857-4867.
Léveillé F, Papadia S, Fricker M, Soriano FX, Bell KFS, Martel M-A, 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, 2623-2635.
O’Leary T, van Rossum MCW & Wyllie DJA (2010). Homeostasis of intrinsic excitability in hippocampal neurones: dynamics and mechanism of the response to chronic depolarization. J Physiol 588, 157-170.
Chen PE, Geballe MT, Katz E, Erreger K, Livesey M, O’Toole KK, Le P, Lee CJ, Snyder JP, Traynelis SF & Wyllie DJA (2008). Modulation of glycine potency in rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. J Physiol 586, 227-245.