Prof Mark Cunningham Inaugural Lecture

Mark Cunningham is the Ellen Mayston Bates Professor of Neurophysiology of Epilepsy at Trinity College Dublin and the Head of the Discipline of Physiology. Hacking the brain’s accelerator: novel therapies for epilepsy? Seizures can be thought of as an electrical storm that occurs in the brain. Any animal with a brain can experience a seizure, be that a human, a dog or even a fly! Imagine for a moment that the brain is made up of a hundred billion nerve cells that are all connected together and all these cells can excite one another meaning that if these were the only nerve cell types the brain would be in a constant seizure state. These cells are termed excitatory neurons. Thankfully for the majority of people a state of constant seizures is not the case. This is due to the presence of another type of nerve cell that regulate this excitability and prevent seizures from occurring. These cells are called inhibitory interneurons. If excitation in the brain is driven too far and becomes uncontrollable then a seizure will occur. This can be the case during the withdrawal of excessive alcohol or certain drugs, it is also observed during electroconvulsive therapy. In epilepsy, seizures occur spontaneously and this is due to changes that have taken place to the excitatory and inhibitory neurons and how they interact with one another. There are a multitude of reasons for why this happens. Damage to the brain caused by various insults (for e.g., physical trauma, tumours, hypoxia) can cause epilepsy. Other causes include the miswiring of small numbers of the brain cells during development or genetic mutations that modify the overall excitability of nerve cells. In many cases the precise cause may be unknown. For the majority of people living with epilepsy their seizures are controlled by the anti-seizure medications they are taking. However, roughly a third of people living with epilepsy do not get adequate control of their seizures despite being on several anti-seizure drugs. For these people epilepsy is a devastating condition marked by unpredictable and severe seizures. There is a significant impact of the disease on the quality of life for these people. Many will suffer from depression, anxiety, impaired memory and impaired cognition and in many cases the side-effects of anti-seizure medication may exacerbate these comorbidities. In attempting to understand the mechanisms underlying seizure activity and how it might be stopped my research has taken a number of different approaches to address this. These include the utilisation of live human tissue from patients with intractable epilepsy, animal models, computational approaches and pharmacology. My research has been focused on the neurotransmitter glutamate. Glutamate acts as an accelerator in the brain, driving excitation. It is an important neurotransmitter for physiological processes in the brain, such as learning and memory and the generation of neuronal oscillations. However, in disease states such as epilepsy, the regulation of glutamate levels and/or changes in the receptors that glutamate acts on can lead to hyperexcitability and the generation of  seizure activity. Such is the case in a particular form of epilepsy that is associated with brain tumours. We now understand that the tumour hijacks glutamate for its own end and uses the neurotransmitter to trigger seizure activity and promote the growth of the tumour.  My lecture will discuss the importance of glutamate for normal function in the brain, how it plays a crucial role in driving seizures and how novel therapies are being developed that target this neurotransmitter system. With support from Science Foundation Ireland my research team at Trinity are now focusing on exploring the efficacy of a gene therapy approach for seizures associated with brain tumours. This work aims to explore if expressing a novel glutamate-gated channel in brain cells around the tumour can selectively inhibit neurons in response to increases in extracellular glutamate concentrations. The aim of this approach is to limit seizure activity and offer a precision based medicine approach for patients with this condition.