Research Projects

Supervisory team

Primary supervisor:Prof David Wyllie (Centre for Discovery Brain Sciences)

Additional supervisors: Prof Emma Wood (Cente for Discovery Brain Sciences)

Funding Notes 

The successful applicant will be awarded a fully-funded 3-year ERUK Doctoral Training Centre studentship which include their stipend and tuition fees, and contributions towards travel and research costs.  

You should hold at least an upper second-class degree or equivalent in a relevant discipline (e.g., cell biology, physiology, pharmacology, neuroscience).  Please apply using the form available here and using the code “ERUK-NMDA” for the project code.  Informal inquiries can be made to david.j.a.wyllie@ed.ac.uk in advance of the closing date of Friday 7^thMarch 2025.

Project Description

• Background

N-methyl-D-aspartate (NMDA) receptors are a class of ligand-gated ion channel that are activated by L-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS).  Physiologically NMDA receptors play critical roles in fast excitatory neurotransmission and signalling, in neurodevelopment, synaptic plasticity while dysfunctional NMDA receptor function leads failure certain forms of learning and memory, cell death via excitotoxicity leading to neurodegenerative disease, and where there is imbalance in the excitation:inhibition ratios this is thought to be a significant factor that leads to several psychiatric disorders.  Importantly for this project impaired NMDA receptor function can give rise to epilepsy. 

Fundamental to the normal physiological functioning of NMDA receptors is the voltage-dependent block that is mediated by Mg²⁺ ions – at resting membrane potentials the permeation pathway (i.e. the ion channel pore) of NMDA receptors is blocked by Mg²⁺ and only when the membrane potential depolarizes as a result of increased electrical activity does the pore become permeable to cations, most notably Na⁺, K⁺ and Ca²⁺ ions.  Without voltage-dependent Mg²⁺ block, NMDA receptors would be active at rest and this would lead to excessive excitatory drive and uncontrolled neuronal activity and potentially massive seizure activity.  Hence, voltage-dependent Mg²⁺ block is critical for normal glutamatergic synaptic function.  In recent years many mutations have been identified in GRIN genes (the genes that encode NMDA receptor subunits) which lead to expression of NMDA receptors with either gain- or loss- of function (1).  

• About the Project

In this PhD project the student will study the effects of a mutation that in humans causes a severe childhood-onset epilepsy (2) and results from the asparagine residue in the GluN2A subunit being replaced by a lysine residue – GluN2A^N615K.  Our lab has previously characterized the physiological and pharmacological properties of GluN2A-containing NMDA receptors harbouring this mutation in heterologous expression systems (3, 4) but in this project we will use a transgenic rat model in which half of the GluN2A NMDA receptor subunits express the mutation – thus the heterozygous nature of the expression seen in humans is reflected in the model.

The student will use multidisciplinary approaches to gain mechanistic understanding of how the reduced voltage-dependent Mg²⁺ block exhibited by NMDA receptors expressing GluN2A NMDA receptor subunits leads to pathophysiological signalling in the CNS.  The N615K mutation can be considered to be both a loss-of-function mutation (reduced Mg²⁺ block and reduced Ca²⁺ permeability) while at the same time it can be thought of as being a gain-of function mutation as the activity of NMDA receptors will not be inhibited at hyperpolarized membrane potentials.  To assess the extent to which these two sides of altered function contribute to dysregulated signalling the student will combine electrophysiological recording from ex vivo brain slices to assess synaptic function and Ca²⁺-imaging to monitor network activity.  Moreover, using a variety of pharmacological seizure-inducing paradigms the student will determine whether this pre-clinical model of childhood-onset epilepsy shows either spontaneous seizure-like activity or increased susceptibility to seizure initiation.  Finally, using in vivo recording the student will assess whether the extent to which this mutation leads to epileptic-like activity and how such activity can be ameliorated by drug interventions.

References

1. XiangWei W, Jiang Y, Yuan H: De Novo Mutations and Rare Variants Occurring in NMDA Receptors. Curr Opin Physiol 2018, 2:27-35.

2. Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortum F, Fritsch A, Pientka FK et al: Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010, 42(11):1021-1026.

3. Marwick KFM, Hansen KB, Skehel PA, Hardingham GE, Wyllie DJA: Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy. J Physiol 2019, 597(6):1691-1704.

4. Marwick KFM, Skehel PA, Hardingham GE, Wyllie DJA: The human NMDA receptor GluN2A(N615K) variant influences channel blocker potency. Pharmacol Res Perspect 2019, 7(4):e00495.

• About the ERUK-DTC

The ERUK-DTC is a virtual centre with principal investigators researching different aspects of childhood-onset epilepsies, spread across the University of Edinburgh.  In addition to your research, you will be trained and nurtured to become an innovative, creative thinker, will be trained in state-of-the-art techniques, will gain insight into the needs and thoughts of patients and their families, and become equipped to engage with audiences within and beyond the research world.  As an ERUK-DTC graduate, you will be ideally placed to be part of the next generation of scientific research leaders in childhood-onset epilepsies.

• About the Supervisors/PI

Prof David Wyllie has a long-standing research interest in physiology, pharmacology and function of ligand-gated ion channels, particularly those activated by the neurotransmitter, L-glutamate.  Through electrophysiological studies, his lab seeks to understand the structure-function properties and physiological roles of the various subtypes of NMDA receptors.   In related research he uses pre-clinical models of single gene causes of neurodevelopmental disorders 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.   

Prof Emma Wood’s research focuses on neural circuits mediating cognition and memory, and how they are affected in rat models of neurodevelopmental disorders such as Fragile X Syndrome and GRIN-related neurodevelopmental disorders. A major focus in the lab is on circuits mediating spatial cognition and spatial memory, which we probe using in vivo electrophysiological recording techniques for measuring the activity of individual neurons and neuronal populations in awake freely behaving rats, combined with behavioural tasks designed to measure specific cognitive abilities. We are particularly interested in how spatially tuned neurons in the brain such as place cells and head direction cells support spatial cognition, memory, and flexibility, and how the juvenile development and function of these circuits are affected in rat models of ASD/ID.

Academic References

Applicants should also arrange for two academic referees to submit letters of reference via email before the deadline to EdNeuro.PhD@ed.ac.uk including “ERUK-NMDA” and your name in the subject.  All documents should be submitted no later than 5pm on Friday 7^th March 2025. Short-listed candidates will be notified by email.