Interneurons in epilepsy
Category: Current
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Harmonious functioning of the brain hinges upon accurate excitatory and inhibitory actions from pyramidal neurons and GABAergic interneurons, respectively. Seizures arise from hyperexcitability of the brain, which may manifest from inadequate GABAergic inhibitory actions. Little is known about inhibitory interneurons and epilepsy, but it is commonly thought that seizures arise from the inadequacy of GABAergic inhibitory actions. It is now clear that this concept is oversimplified. Recent evidence demonstrates that in epileptic brain tissue, GABAergic networks undergo complex rewiring at anatomical, physiological and functional levels. These novel results indicate that the role of GABAergic interneurons in epilepsy is more complicated than can be explained just by a reduction or absence of inhibitory activity. The aim of this project is to investigate interneuron properties in an epileptic mouse model using immunohistochemical and electrophysiological techniques. Our laboratory has produced, and is characterising, the first transgenic (knock-in) mouse model carrying a human epilepsy mutation (R43Q) on the GABAA receptor 2 subunit (GABRG2(R43Q)). GABAergic interneurons make up around 20% of neurons in the brain and are difficult to identify. To overcome this limitation, in this project, we will cross our existing epileptic mouse with a transgenic mouse that expresses green fluorescent protein (GFP) in all interneurons, thus allowing the identification of interneurons in the brain. Using the R43Q mouse model of absence epilepsy, this project will investigate interneuron properties in two regions involved in the thalamocortical circuit, the reticular thalamic nucleus (NRT) and the somatosensory cortex. The neurochemical properties, electrical properties and connectivity of these green fluorescing interneurons will be characterised in wildtype and epileptic mice to determine whether interneuron development (migration, morphology and syaptic bouton density) and function is altered in our epilepsy mutant mice.. Analysis of GABA-releasing inhibitory interneurons in R43Q mice will provide insights into the underlying mechanisms leading to the generation of absence seizures. This study will provide a rationale as to how the R43Q mutation in the GABAA receptor 2 subunit alters electrical network activity in the brain to cause epilepsy.
