Neurophysiology of Excitable Networks Group
Our group is dedicated to understanding how neurons become excited, particularly in epilepsy. Epilepsy can have a major impact on the lives of patients and their caregivers. Although treatment is available, it doesn’t always work well and can lead to unpleasant side-effects. This is especially true for certain childhood epilepsies known as developmental and epileptic encephalopathies. To help these patients, we need to learn more about their condition. Currently, around 70% of severe childhood epilepsies have a known genetic cause, which means we can start by investigating the underlying mechanisms of the disease.
We use different methods, including rodent models based on human mutations, to study the disease. These models have helped us identify potential targets for precise medicines, and have also helped us determine which anti-seizure medications are most effective. We have also identified how mutated proteins can lead to other medical issues. Epilepsy patients are at an increased risk of sudden unexpected death (SUDEP), which is why we have developed rodent models with a genetic link to SUDEP. We use these models to test drugs that may reduce the incidence of SUDEP. Our research has already helped many patients, and our goal is to continue to build on our success to help even more epilepsy patients and their caregivers.
About our research
Epilepsy affects up to 4% of the population at some time in their lives. There are major challenges in clinical epilepsy care with at least 30% of patients resistant to current therapies. Even among those patients whose seizures are controlled, major issues of drug side-effects and co-morbidities often affect quality of life. Clinical and geneticist colleagues have discovered more than 30 genes associated with epilepsy with more being discovered each month. However, knowing the genetic cause of epilepsy is not enough to tell you how seizures or epilepsy co-morbidities (e.g. learning difficulties) occur. A mutation in a protein can have its impact on several temporal and spatial scales and understanding the cellular consequence of these changes is central to our understanding, and eventual treatment, of epilepsy. We use a range of experimental techniques to investigate dysfunction at each of these scales. In particular we use brain-slice electrophysiology methods to directly measure neuronal excitability. We also use state-of-the-art imaging and molecular methods.
Our group’s major recent discoveries have come in understanding the genetic epilepsies. Using mouse models of epilepsy based on human mutations, we’ve identified new disease mechanisms (Brain 2021, Brain 2014), as well as explaining some of the complexity of the genetic architecture of the epilepsies (Nature Reviews Neurology 2022, Pharmacological Reviews 2018, Neurology 2013). Evidence that targeted therapy based on cellular mechanism can be effective in these rodent models (Epilepsia 2023) exemplifies an exciting paradigm in which precision medicine in the epilepsies can advance. Our group is also investigating the role of genetic risk factors in sudden unexpected death in epilepsy and has recently provided evidence that variants in major genes that affect heart rhythm can increase risk in susceptible individuals (Epilepsia 2022, Annals of Clinical and Translational Neurology 2021).
- Excitable networks
- Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels
- Ion channels- disease mechanism and biophysics
- Drug screening and discovery
- Precision medicine
- Sudden unexpected death in epilepsy
- Mouse behaviour (cognition, social, motor, general)
- In vivo electrophysiology (video EEG-ECG)
- In vitro/ex-vivo electrophysiology (brain-slice patch-clamp, whole-cell patch clamp, medium-throughput Patchliner, two-electrode voltage-clamp)
- Molecular techniques (electroporation)
- Immunohistochemistry and imaging
- Cell culture
- Stem cells
- Biophysics of leaky HCN ion channels
- Finding a cure for a devastating form of epilepsy
- Novel antiepileptic drug targets based on HCN channel antagonists
- Pacemaker channels and brain excitability
- Using novel animal models to investigate the role of genetic cardiac arrhythmia in sudden unexpected death in epilepsy (SUDEP)
- Chaseley McKenzie
- James Spyrou
- Hian Mun Lee
Research and technical staff
- Alibek Kuanyshbek
- Bleakley, L.E., McKenzie, C.E. and Reid, C.A. (2022). Efficacy of antiseizure medication in a mouse model of HCN1 developmental and epileptic encephalopathy. Epilepsia, 64(1). doi:https://doi.org/10.1111/epi.17447.
- Bleakley, L.E., McKenzie, C.E., Soh, M.S., Forster, I.C., Paulo Pinares-Garcia, Sedo, A., Anirudh Kathirvel, Leonid Churilov, Nikola Jancovski, Snezana Maljevic, Berkovic, S.F., Scheffer, I.E., Petrou, S., Santoro, B. and Reid, C.M. (2021). Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy. Brain, 144(7), pp.2060–2073. doi:https://doi.org/10.1093/brain/awab145.
- Hung, A., Forster, I.C., Mckenzie, C.E., Berecki, G., Petrou, S., Kathirvel, A., Soh, M.S. and Reid, C.A. (2021). Biophysical analysis of an HCN1 epilepsy variant suggests a critical role for S5 helix Met-305 in voltage sensor to pore domain coupling. Progress in Biophysics and Molecular Biology, [online] 166, pp.156–172. doi:https://doi.org/10.1016/j.pbiomolbio.2021.07.005.
- Soh, M.S., Bagnall, R.D., Bennett, M.K., Bleakley, L.E., Syazwan, M., Phillips, A.N., Mathew, McKenzie, C.E., Hildebrand, M.S., Crompton, D.E., Bahlo, M., Arthur A.M. Wilde, Scheffer, I.E., Berkovic, S.F. and Reid, C.M. (2021). Loss‐of‐function variants in K v 11.1 cardiac channels as a biomarker for SUDEP. Annals of clinical and translational neurology, 8(7), pp.1422–1432. doi:https://doi.org/10.1002/acn3.51381.
- Oyrer, J., Maljevic, S., Scheffer, I.E., Berkovic, S.F., Petrou, S. and Reid, C.A. (2018). Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies. Pharmacological Reviews, [online] 70(1), pp.142–173. doi:https://doi.org/10.1124/pr.117.014456.