Prof David Wyllie

We study neurotransmitter action in central neurons to understand normal synaptic function and its dysfunction in models of neurodevelopmental and neurodegenerative diseases.

Professor David Wyllie

Professor of Ion Channel Physiology and Pharmacology; Director, Centre for Discovery Brain Sciences

Hugh Robson Building

15 George Square

Edinburgh, EH8 9XD

Contact details

 Work: +44 (0)131 650 4564

 Email: david.j.a.wyllie@ed.ac.uk

 

Personal profile

2018 - Present: Senior Editor, The Journal of Physiology

2017 - Present: Director, Centre for Discovery Brain Sciences

2015 - 2018:  Reviewing Editor, The Journal of Physiology

2015 - 2017: Director, Centre for Integrative Physiology

2008 - 2011:  Member, Wellcome Trust Molecular & Cellular Neuroscience Funding Committee

2006 - 2014:  Trustee of The Physiological Society

2002 - 2009:  Editorial Board Member, British Journal of Pharmacology

1994 - 1999:  Royal Society University Research Fellow, Dept of Pharmacology, UCL

1992 - 1994:  SERC/NATO post-doctoral researcher, Dept of Pharmacology, University of California, San Francisco

Research Theme

Synapses, Circuits and Behaviour

Injury and Repair

Research

Prof David Wyllie's research briefing

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.

Funding

We gratefully acknowledge present and past support for our research from the following:

Medical Research Council (MRC)

Biotechnology and Biological Sciences Research Council (BBSRC)

Epilepsy Research UK

Lou Lou Foundation

Team members

Kosala Dissanayake (Postdoctoral Fellow)

Katie Marwick (NES/CSO Postdoctoral Clinical Lecturer) 

Nina Petrovic (PhD Student)

Collaborations

Prof Peter Kind (University of Edinburgh)

Prof Giles Hardingham (University of Edinburgh)

Prof Siddharthan Chandran (University of Edinburgh)

Dr Emma Wood (University of Edinburgh)

Dr Matt Livesey (University of Sheffield)

Prof Sumantra Chattarji (Centre for Brain Development and Repair, Bangalore, India)

Prof Derek Bowie (McGill University, Montreal, Canada)

Selected Publications

Booker SA, Sumera A, Kind PC & Wyllie DJA (2021). Contribution of NMDA receptors to synaptic function in rat hippocampal interneurons. ENEURO.0552-20.2021  doi: 10.1523/ENEURO.0552-20.2021 PMID: 34326063

Perkins EM, Burr K, Banerjee P, Mehta AR, Dando O, Selvaraj BT, Suminaite D, Nanda J, Henstridge CM, Gillingwater TH, Hardingham GE, Wyllie DJA, Chandran S & Livesey MR (2021). Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction. Mol Neurodegener 16(1):13. doi: 10.1186/s13024-021-00433-8  PMID: 33663561

Booker SA, Simões de Oliveira L, Anstey N, Kozic Z, Dando OR, Jackson AD, Baxter PS, Isom LL, Sherman D, Hardingham GE, Brophy PJ, Wyllie DJA & Kind PC (2020). Input-output relationship of CA1 pyramidal neurons reveals intact homeostatic mechanisms in a mouse model of fragile X syndrome Cell Rep 32:107988. doi: 10.1016/j.celrep.2020.107988  PMID: 32783927

Das Sharma S, Pal R, Reddy BK, Selvaraj BT, Raj N, Samaga KK, Srinivasan DJ, Ornelas L, Sareen D, Livesey MR, Bassell GJ, Svendsen CN, Kind PC, Chandran S, Chattarji S & Wyllie DJA (2020).  Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns. Mol Autism 11 52. doi: 10.1186/s13229-020-00351-4.  PMID: 32560741

Booker SA, Domanski APF, Dando O, Jackson AD, Isaac JTR, Hardingham GE, Wyllie DJA & Kind PC (2019).  Altered dendritic spine function and integration in a mouse model of fragile X syndrome. Nat Commun 10 4813 doi: 10.1038/s41467-019-11891-6.  PMID: 31645626

Domanski APF, Booker SA, Wyllie DJA, Isaac JTR & Kind PC (2019).  Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex.  Nat Commun 10 4814 doi: 10.1038/s41467-019-12736-y. PMID: 31645553

Asiminas A, Jackson AD, Louros SR, Till SM, Spano T, Dando O, Bear MF, Chattarji S, Hardingham GE, Osterweil EK, Wyllie DJA, Wood ER & Kind PC (2019).  Sustained correction of associative learning deficits following brief, early treatment in a rat model of Fragile X Syndrome. Sci Transl Med 11 eaao0498.  PMID: 31142675

Marwick KFM, Hansen KB, Skehel PA, Hardingham GE & Wyllie DJA (2019).  Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy. J Physiol 597, 1691-1704.  PMID: 30604514

Strehlow V, Heyne HO, Vlaskamp DRM, Marwick KFM, Rudolf G, de Bellescize J, Biskup S, Brilstra EH, Brouwer OF, Callenbach PMC, Hentschel J, Hirsch E, Kind PC, Mignot C, Platzer K, Rump P, Skehel PA, Wyllie DJA, GRIN2A study group, Hardingham GE, van Ravenswaaij-Arts CMA, Lesca G & Lemke JR. (2019).  Genotype-phenotype correlation of 247 individuals with GRIN2A-related disorders identifies two distinct phenotypic subgroups associated with different classes of variants, protein domains and functional consequences. Brain 142, 80-92. PMID: 30544257

McKay S, Ryan TJ, McQueen J, Indersmitten T, Marwick KFM, Hasel P, Kopanitsa MV, Baxter PS, Martel M-A, Kind PC, Wyllie DJA, O'Dell TJ, Grant SGN, Hardingham GE & Komiyama NH. (2018). The developmental shift of NMDA receptor composition proceeds independently of GluN2 subunit-specific GluN2 C-terminal sequences Cell Rep 25, 841-851.  PMID: 30355491

Selvaraj BT, Livesey MR, Zhao C, Gregory J, James OT, Cleary  EM, Chouhan AK, Gane A, Perkins EM, Dando O, Lillico SG, Lee Y-B, Nishimura AL, Poreci U, Thankamony S, Pray M, Vasistha NA, Magnani D, Borooah S, Burr K, Story D, McCampbell A, Shaw CE, Kind PC, Aitman TJ, Whitelaw CBA, Wilmut I, Smith C, Miles GB, Hardingham GE, Wyllie DJA & Chandran S (2018).  C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity. Nat Commun 9, 347 doi: 10.1038/s41467-017-02729-0 PMID: 29367641

McQueen J, Ryan TJ, McKay S, Marwick K, Carpanini S, Wishart TM, Gillingwater TH, Manson JC, Wyllie DJA, Grant SGN, McColl B, Komiyama NH & Hardingham GE (2017).  Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of DAPK1. eLife  6:e17161 PMID: 28731405