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Full NameProfessor Mark Cunningham
Department:Discipline of Physiology
Organisation:Trinity College Dublin
- physiology and non-communicable disease
- neuroscience and mental health
The Cunningham research group works to gain a better understanding of the mechanisms that contribute to the generation of organised electrical activity in the brain in health and disease states. In the lab we primarily use electrophysiology to study the mechanisms by which neuronal microcircuits give rise to neuronal oscillations in the brain. Our work has implications for conditions such as neurodegeneration and schizophrenia. The lab has a particular interest in understanding how pathological electrical activity arises in the epileptic brain and we use our approaches to develop better treatments for epilepsy.
Chan F, Lax NZ, Voss CM, Aldana BI, Whyte S, Jenkins A, Nicholson C, Nichols S, Tilley E, Powell Z, Waagepetersen HS, Davies CH, Turnbull DM, Cunningham MO. The role of astrocytes in seizure generation: insights from a novel in vitro
seizure model based on mitochondrial dysfunction. Brain. 2019 doi: 10.1093/brain/awy320.
Augustin K, Williams S, Cunningham M, et al. Perampanel and decanoic acid show synergistic action against AMPA receptors and seizures. Epilepsia. 2018;59(11):e172-e178. doi:10.1111/epi.14578
Stone TJ, Rowell R, Jayasekera BAP, Cunningham MO, Jacques TS. Review: Molecular characteristics of long-term epilepsy-associated tumours (LEATs) and mechanisms for tumour-related epilepsy (TRE). Neuropathol Appl Neurobiol. 2018 doi: 10.1111/nan.12459.
Jones RS, da Silva AB, Whittaker RG, Woodhall GL, Cunningham MO. Human brain slices for epilepsy research: Pitfalls, solutions and future challenges. J Neurosci Methods. 2016 doi: 10.1016/j.jneumeth.2015.09.021.
The neurotransmitter glutamate plays a key role in brain tumour related epilepsy (BTRE). This suggests that components of the glutamate system can be targeted to limit seizure generation. Therapeutic avenues have been explored in human studies and animal models. The pharmacological targeting of glutamate receptors has shown potential, particularly with AMPA receptor (AMPAr) blockers. Early versions of non-competitive AMPAr antagonists (for e.g. talampanel) were explored as drugs for the treatment of epilepsy. Talampanel has poor pharmacokinetics and a significant side effect profile. A similar drug, perampanel (EMA & FDA approved for partial-onset seizures), is currently being examined in BTRE patients (ClinicalTrials.gov Identifier: NCT02363933). Data from a observational study of the efficacy of perampanel on seizures in patients with BTRE is promising, with reports of seizure freedom in 6 (out of 12) patients. However, perampanel displays significant side effects in clinical practice and this is due to the non-specific action of the drug on AMPAr. AMPAr facilitate synaptic transmission between neurons. This underlies physiological processes such as learning and memory. The AMPAr comes in 2 forms. AMPAr possessing the GluA2 subunit are predominantly permeable to sodium ions and are highly expressed on excitatory neurons. AMPAr lacking the GluA2 subunit are termed calcium permeable AMPAr (CP-AMPAr) and are found in pathological conditions. We hypothesise that insults inflicted by the tumour on peritumoural neurons cause excitatory cells in this area to express calcium permeable AMPAr via a long-lasting down-regulation of GluA2. We hypothesise that the down regulation of GluA2 in pyramidal neurons permits these cells to be targeted via compounds which antagonise CP-AMPAr and that this will aid in a precision medicine based approach to treat BTRE. The project will aim to test if targeting CP-AMPAr will provide a more precise target for novel therapeutics for BTRE.