Research Projects

This Doctoral Training Centre offers research PhDs in childhood-onset epilepsies.

Applications are now closed. See below for ongoing projects.  

Supervisory team

Primary supervisor: Prof Cathy Abbott (Institute of Genetics and Cancer)

Additional supervisors:  Dr Alfredo González Sulser (Centre for Discovery Brain Sciences)


  • Background

The ease of use of gene editing tools developed over the last 5 years has resulted in many new models of genetic epilepsies that recapitulate clinical mutations precisely . However, in spite of the severity of the conditions being modelled, these new mouse lines frequently display phenotypic abnormalities but stop short of showing face validity in the form of spontaneous seizures, at least at a high enough frequency to be readily observable. Clearly any therapeutic strategy (whether genetic or drug-based) needs to be tested on suitable animal models, but the translational potential of such studies is limited if there is no ability to test the impact of the intervention on seizures.

  • About the Project

In this project the student will explore several different approaches to solving the problem of low frequencies/absence of spontaneous seizures in the context of one to two specific genes in which de novo mutations cause childhood-onset epilepsy (such as EEF1A2 and CDKL5), and for which well characterised mouse models are available. The use of multiple lines will allow the student to make direct comparisons and judge how widely applicable any specific approach would be. They will explore a range of different methods to enhance face validity including continuous EEG monitoring, in-cage behavioural monitoring coupled with video recording, altering the genetic background of the parent strain, and measuring the threshold for seizure induction.

The student will, in parallel, also investigate molecular mechanisms underlying at least one of these genetic disorders; this could range from the use of proteomics to look at changes in binding partners resulting from specific mutations, to detailed characterisation of expression patterns in specific neuronal populations and/or mapping expression throughout the brain using lightsheet microscopy. This combination of sub-projects will allow the student to be trained in a wide variety of lab disciplines from basic to preclinical research. This approach will also allow the student to generate their own hypotheses to be tested in the later stages of the PhD. They will thus combine important research into practical solutions for the development of face valid preclinical models to maximise their translational potential, with more fundamental research into mechanisms underlying childhood-onset epilepsies.


1. Fallah MS, Eubanks JH. Seizures in mouse models of rare neurodevelopmental disorders. Neuroscience. 2020 Feb 12;

2. Davies FCJ, Hope JE, McLachlan F, Marshall GF, Kaminioti-Dumont L, Qarkaxhija V, et al. Recapitulation of the EEF1A2 D252H neurodevelopmental disorder-causing missense mutation in mice reveals a toxic gain of function. Hum Mol Genet. 2020 Jun 27;29(10):1592–1606.

3. Amendola E, Zhan Y, Mattucci C, Castroflorio E, Calcagno E, Fuchs C, et al. Mapping pathological phenotypes in a mouse model of CDKL5 disorder. PLoS One. 2014 May 16;9(5):e91613.

4. Marshall G, Gonsalez-Sulser A, Abbott CM. Modelling epilepsy in the mouse: challenges and solutions. Dis Model Mech 2021. 14(3):dmm047449. doi: 10.1242/dmm.047449

Supervisory team

Primary supervisor: Prof Emily Osterweil (Centre for Discovery Brain Sciences)

Additional supervisors:  Prof Matt Nolan (Centre for Discovery Brain Sciences)


  • Background

Childhood-onset epilepsy is a feature of several neurodevelopmental disorders, including Fragile X Syndrome and SYNGAP1 haploinsufficiency, two monogenic causes of autism and intellectual disability1,2. The aetiology of seizures in these disorders is poorly understood. However, treatments that normalize protein synthesis have been shown to prevent the emergence of pathological changes in both Fmr1-/y and Syngap+/- mouse models, including epileptiform activity and susceptibility to audiogenic seizures (AGS) 3-6. This suggests that dysregulation of protein turnover causes the generation of epilepsy (epileptogenesis) in both disorders.

Identifying the functional consequences of dysregulated protein turnover that contribute to epileptogenesis could provide unique insights and potentially identify new therapeutic targets. The student will use cutting edge techniques in molecular biology, electrophysiology and imaging to assess the functional consequences of changes in protein synthesis and degradation that occur within seizure-generating neurons.

  • About the Project

The specific aims are to: (1) elucidate the critical neuron populations contributing to AGS in Fmr1-/y and Syngap+/- rat models, and (2) to identify the functional changes that occur as a results of dysregulated protein synthesis and degradation in these neurons and that contribute to seizure generation

Although AGS is a highly reproducible phenotype in the Fmr1-/y and Syngap+/- models, the underlying circuitry has not been identified. To identify activated neurons over a time-course post-AGS induction, the student will use a combination of immunostaining for cFos (which reports recently active neurons) and whole-brain imaging. This approach will enable the student to focus on detailed analysis of brainstem nuclei implicated in audiogenic seizures in other models and unbiased brain-wide analyses to capture a global picture of candidate neural populations. The student will then use animals treated with lovastatin, a therapeutic that prevent AGS in the Fmr1-/y model, to more discretely identify the circuits that generate seizure activity 4.

To understand how  contributes to epileptogenesis,  brain slice patch-clamp electrophysiology approaches will be used to identify ion channel mechanisms active in the candidate neuronal populations that lead to seizure generation. This strategy will take advantage of TRAP-seq profiling and proteomic data from the Osterweil lab, which has  reveal novel targets for therapeutic intervention in developmental disorders and childhood-onset epilepsies7. The initial focus will be  on excitatory neurons in the Inferior Colliculus that have been implicated in AGS 8. The ion channel mechanisms that promote epileptogenesis in mutant neurons will then be targeted for knock-down using viral injection of shRNAs or using relevant pharmacological strategies.


1. Berry-Kravis, E. Epilepsy in fragile X syndrome. Dev Med Child Neurol 44, 724-728 (2002).

2. Mignot, C. et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. Journal of medical genetics 53, 511-522, doi:10.1136/jmedgenet-2015-103451 (2016).

3. Yan, Q. J., Rammal, M., Tranfaglia, M. & Bauchwitz, R. P. Suppression of two major Fragile X Syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49, 1053-1066, doi:10.1016/j.neuropharm.2005.06.004 (2005).

4. Osterweil, E. K. et al. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77, 243-250 (2013).

5. Barnes, S. A. et al. Convergence of Hippocampal Pathophysiology in Syngap+/- and Fmr1-/y Mice. J Neurosci 35, 15073-15081, doi:10.1523/JNEUROSCI.1087-15.2015 (2015).

6. Wang, C. C., Held, R. G. & Hall, B. J. SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PLoS One 8, e83941, doi:10.1371/journal.pone.0083941 (2013).

7. Thomson, S. R. et al. Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome. Neuron 95, 550-563 e555, doi:10.1016/j.neuron.2017.07.013 (2017).

8. Gonzalez, D. et al. Audiogenic Seizures in the Fmr1 Knock-Out Mouse Are Induced by Fmr1 Deletion in Subcortical, VGlut2-Expressing Excitatory Neurons and Require Deletion in the Inferior Colliculus. J Neurosci 39, 9852-9863, doi:10.1523/JNEUROSCI.0886-19.2019 (2019).

Supervisory team

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

Additional supervisors: Dr. Katie Marwick (Centre for Clinical Brain Sciences)


  • 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 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 – GluN2AN615K.  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.


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.

Primary supervisor:Prof Richard Chin (Department of Child Life and Health, Centre for Clinical Brain Sciences)

Additional supervisors: Dr. Bonnie Auyeung (School of Philosophy, Psychology and Language Sciences)


  • Background

Childhood-onset epilepsies, forty percent of which are due to monogenic causes (1), are associated with negative sequela across the lifespan, including poor academic achievement, difficulties with social and behavioural functioning, and high rates of unemployment.  Early identification of cognitive and or behavioural problems in childhood-onset epilepsies, provides opportunities for early intervention for those affected that may have long-lasting positive effects on their later life.  However, cognitive and or behavioural problems in childhood-onset epilepsies are often undiagnosed and or poorly managed (2).  The outcomes of children of women with epilepsy remains unclear as most studies on the topic focus mainly or exclusively on antiseizure medication exposure during pregnancy.

Not all cognitive and or behavioural problems may be present at the time of epilepsy diagnosis so periodically screening for such problems is paramount (3).  Further, some children will have improvement in their cognitive and or behavioural problems after epilepsy diagnosis and adequate seizure control, whilst others will have persistent problems despite good seizure control and others will have persistent problems along with seizures that are refractory to treatments.  Thus, neurodevelopmental trajectories in childhood-onset epilepsies may vary.  

We have established a unique Scottish cohort (N=59) of well-phenotyped early-onset childhood epilepsies (onset before age five years of age) diagnosed between May 2013 and June 2015.  There are early initial psychometric neurodevelopmental data within 3 months of diagnosis, concomitant diagnostic MRI and EEG data, and genetic information available for the cohort.  Fifty percent of children in that cohort had learning and or behavioural comorbidities on initial testing.  Results were fed back to their respective clinicians, but it is uncertain if any interventions resulted. It is also unknown if any have improved or if any have developed cognitive and or behavioural problems since the initial study.   We are also able to link Scottish national health and educational datasets and would be well placed to examine the outcomes of large scale cohorts of children followed from birth and according to whether they were diagnosed with epilepsy or not, and the children of pregnant women with epilepsy.

  • About the Project

We hypothesise: (1)  more than 50% of children with early-onset epilepsy will have cognitive/behavioural problems at 6-8 years follow-up after epilepsy diagnosis, and will have lower educational attainment compared to peers; (2) children of women with epilepsy, irrespective of whether they were on antiseizure medication during pregnancy,  will have lower educational attainment compared to children of women without epilepsy; (3)  a combination of clinical, sociodemographic, EEG, imaging and genetic factors would enhance the prediction of outcomes.

The specific aims of this studentship are to determine:

  1. the psychological and educational outcomes of children with epilepsy 
  2. educational outcomes of children of women with epilepsy
  3. risk factors for poor outcomes for 1 and 2.

Thus, this project will provide the student with well-rounded multi-disciplinary training in clinical epidemiology, neurodevelopmental psychology, and statistics, and allow the student to develop innovative, potentially life-changing ways to inform streamlining of treatments for cognitive and or behavioural problems in childhood-onset epilepsies and offsoirng of women with epilepsy. 


1. Zhang D, Liu X, Deng X. Genetic basis of pediatric epilepsy syndromes. Exp Ther Med. 2017 May;13(5):2129-2133. doi: 10.3892/etm.2017.4267. Epub 2017 Mar 27. PMID: 28565819; PMCID: PMC5443213.

2. Reilly C, Atkinson P, Das KB, Chin RF, Aylett SE, Burch V, Gillberg C, Scott RC, Neville BG. Neurobehavioral comorbidities in children with active epilepsy: a population-based study. Pediatrics. 2014 Jun;133(6):e1586-93

3. Nickels, K., Zaccariello, M., Hamiwka, L. et al. Cognitive and neurodevelopmental comorbidities in paediatric epilepsy. Nat Rev Neurol 12, 465–476 (2016).

Supervisory team

Primary supervisor:Javier Escudero (School of Engineering)

Additional supervisors: Dr Alfredo González Sulser (Centre for Discovery Brain Sciences)


  • Background

The spontaneous occurrence of epileptic seizures has been found to be dependent on circadian and ultradian rhythms(1). Recent data science advances to characterise multivariate time series have shown promise in predicting and detecting seizures. The ability to predict seizures reliably would be highly beneficial to enable timed interventions or improve quality of life by allowing patients to plan for safe conditions when seizures are more likely.

  • About the Project

This project aims to shed light on how diverse physiological characteristics interact with circadian and ultradian rhythms to promote the occurrence of seizures. The student will test the hypotheses that circadian and ultradian patterns affect the likelihood of seizures in humans and rodent models of childhood-onset epilepsy; and that algorithms can learn the interactions of those rhythms with brain activity features for more accurate seizure prediction.

The student will be trained on algorithms to explore what collection of variables in continuous brain activity predicts seizures and whether these are dependent on circadian and ultradian patterns. The recent open-access availability of published algorithms facilitates this task and contributes to the open science aspects of this project.

In parallel, the student will be trained in the physiological mechanisms underpinning the origin of seizures in chronic-recording high-channel count childhood-onset epilepsy rodent models, such as the Syngap1 happloinsufficency rat model which displays spontaneous absence seizures and concurrent sharp-wave discharges.

The student will therefore acquire in-depth computational and physiological knowhow by working in parallel with animal and human EEGs(2). Relevant human EEG recordings are publicly available from, a data-sharing platform including intracranial recordings, and, a database purposely recorded to address environmental aspects affecting seizures(3).

A key advantage of our methodology is that the animal models provide robust, consistent recordings upon which the student will master their computational skills before attempting analysis on more complex human data. Furthermore, the training will have a strong translational focus. The results of the computational analyses of animal data and the corresponding physiological knowledge will allow the student to develop further hypotheses about what variables (e.g., spectral changes or altered brain connectivity) are more likely to lead to seizures during certain periods of the day or week, and to test these hypotheses on additional data.

The student’s work will be complementary to previous efforts in the study of circadian and ultradian patterns in seizures, which has thus far not been performed in long-term recordings from well-defined animal models. The work will also delve into recent advances in machine learning algorithms.

Thus, this project provides the student with an exciting opportunity to receive multi-disciplinary cross-centre training in data science and computational models, while simultaneously exploring different forms of epilepsy, the physiology of the nervous system and the effects of circadian and ultradian rhythms in seizures.



(1) Karoly PJ, Goldenholz DM, Freestone DR, Moss RE, Grayden DB, Theodore WH, Cook MJ. …, Cook. Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study. Lancet Neurol. 2018 Nov;17(11):977-985.

(2) Katsanevaki D. Till SM. Buller-Peralta I. Watson TC. Nawaz MS. Arkell D. Tiwari S, Kapgal V. Biswal S, Smith JAB, Anstey NJ, Mizen L, Perentos N, Jones MW, Cousin MA, Chattarji S, Gonzalez-Sulser A, Hardt O, Wood ER, Kind PC.  Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes.

(3) Kuhlmann L, Karoly P, Freestone DR, Brinkmann BH, Temko A, Barachant A, Li F, Titericz G Jr, Lang BW, Lavery D, Roman K, Broadhead D, Dobson S, Jones G, Tang Q, Ivanenko I, Panichev O, Proix T, Náhlík M, Grunberg DB, Reuben C, Worrell G, Litt B, Liley DTJ, Grayden DB, Cook MJ. crowd-sourcing reproducible seizure prediction with long-term human intracranial EEG. Brain. 2018 Sep 1;141(9):2619-2630

Supervisory team

Primary supervisor: Prof Mike Cousin (Centre for Discovery Brain Sciences)

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


  • Background

Forty percent of childhood-onset epilepsies are genetic, most of which are typically monogenic and frequently have a defect in synaptic function at their core. Presynaptic dysfunction is emerging as an important convergence point these disorders (1). The presynapse releases chemical neurotransmitters in response to action potential stimulation and neurotransmitter release is sustained by synaptic vesicle (SVs) endocytosis, defects in which can result in childhood-onset epilepsy (1).  

Mutations in the gene encoding the protein kinase cyclin-dependent kinase-like 5 (CDKL5) result in a childhood-onset epilepsy called CDKL5 deficiency disorder (CDD). We have key unpublished data demonstrating that SV endocytosis is specifically disrupted in CDKL5 knockout neurons. This defect is rescued by expression of wild-type, but not kinase-dead, CDKL5. Therefore, the protein kinase activity of CDKL5 is required for SV endocytosis.

CDKL5 phosphorylates the endocytosis protein amphiphysin at Ser-293 in vitro (2), however we found the phosphorylation status of this residue is unchanged in CDKL5 knockout neurons (unpublished). Therefore, CDKL5 must phosphorylate an unidentified substrate to control SV endocytosis.

  • About the Project

We hypothesise that dysfunction in CDKL5-dependent protein phosphorylation underpins presynaptic dysfunction and contributes to CDD.       

The project aims to

1)   Identify and validate new presynaptic CDKL5 substrates

2)   Confirm their role in SV endocytosis

3)   Link SV endocytosis dysfunction to behavioural phenotypes in CDKL5 knockout animals

Aim 1) Presynaptic CDKL5 substrates will be identified using a phospho-proteomic screen of synaptosomes prepared from both (resting and stimulated) wild-type and CDKL5 knockout hippocampal neuronal cultures. The altered phosphorylation status of three candidates (selected on known roles in SV recycling) will be validated using either custom-made phospho-specific antibodies or immunoprecipitation of candidates and probing with anti-Ser/Thr antibodies.

Aim 2) Molecular replacement experiments will be performed via shRNA-mediated depletion of the endogenous candidate and co-expression of exogenous phospho-null or –mimetic forms. These will be performed in both wild-type and CDKL5 knockout neurons to determine whether occlusion or rescue of the endocytosis phenotype occurs. The student will have the option of performing GST-pull downs from nerve terminal lysates using phospho-null and –mimetic candidates to determine the consequence of CDKL5 phosphorylation on its molecular interactions. 

Aim 3) The student will choose to investigate the effect of manipulation of the substrate phosphorylation status on either neurotransmission (using slice electrophysiology) or behaviour (active place avoidance test) via viral delivery of phospho-null and –mimetic forms of the candidate into the hippocampus of either wild-type or CDKL5 knockout rats.

Specific branch points will be present to allow the student scope to develop the project direction. It also has a range of contingencies. If aim1 is negative, specific endocytosis proteins with CDKL5 consensus sites (RPXS) (3) will be investigated. If aim 2 is negative, the ability of an endocytosis accelerator (maxipost, unpublished) to correct defects in CDKL5 knockout neurons will be determined. The effect of this drug in primary neuronal culture, neurotransmission / behaviour will then be examined.

This will provide the student with training in a palette of state-of-the-art molecular neuroscience techniques to determine the role of a key epilepsy gene, CDKL5, in synaptic and circuit function. 


1.            Bonnycastle K, Davenport EC, Cousin MA. Presynaptic dysfunction in neurodevelopmental disorders: Insights from the synaptic vesicle life cycle. Journal of neurochemistry. 2020.

2.            Sekiguchi M, Katayama S, Hatano N, Shigeri Y, Sueyoshi N, Kameshita I. Identification of amphiphysin 1 as an endogenous substrate for CDKL5, a protein kinase associated with X-linked neurodevelopmental disorder. Archives of biochemistry and biophysics. 2013;535(2):257-67.

3.            Baltussen LL, Negraes PD, Silvestre M, Claxton S, Moeskops M, Christodoulou E, et al. Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics. The EMBO journal. 2018;37(24).