Presynaptic ion channel dysfunction in the forebrain

Epilepsy and migraine are common and frequently disabling diseases that often do not respond to available medication. They both show a strong genetic influence, and most of the genes that have been identified to cause epilepsy or migraine encode proteins that mediate the flux of charged ions across the membranes of neurons. How abnormalities of these proteins cause episodic disturbances of brain function is not known. Although some progress has been made in documenting whether individual mutations increase or decrease the flux of ions, and under which conditions, the consequences for neuronal firing and signalling among neurons remain incompletely understood. Our work addresses these questions by applying advanced optical and electrical measurements to individual neurons in the brain.

Idiopathic epilepsy and related paroxysmal disorders such as migraine represent an immense burden to the individual and to society. Ion channel dysfunction is thought to underlie much of the risk to the individual of developing these diseases. Monogenic channelopathies, manifesting as epilepsy, migraine or episodic ataxia, offer a unique window into the mechanisms by which altered ion channel function can give rise to paroxysmal CNS diseases. Although much is known about how disease-associated mutations affect the function of ion channels in heterologous expression, the consequences of these abnormalities for neuronal function in situ are poorly understood. The goal of the proposed work is to shed light on how mutations of two presynaptic ion channels (Kv1.1 and CaV2.1) affect action potential integration and neurotransmitter release in the hippocampus. We will apply advanced optical and electrophysiological methods, which we have recently optimised to examine mossy fibre signalling, in animal models of diseases caused by mutations of these channels. This work promises to shed light both on the normal roles of K+ and Ca2+ channels in the forebrain and how abnormalities in these channels can lead to seizures and other paroxysmal disturbances of brain function.