Kainic acid-induced seizures in vitro and ex vivo as a model of epilepsies: Rodent primary neurons, acute and organotypic hippocampal slices

Abstract

Epilepsy is a neurological disease that is a worldwide health burden as over 65 people suffer from it. It is caused by overexcitation in the brain that results from dysfunction in the glutamatergic signalling. When glutamate accumulates in the synaptic cleft, glutamate receptors such as AMPA, NMDA and kainate receptors are overactivated and seizure events occur. Seizures are also known to cause morphological changes in the brain such as cell death, hippocampal sclerosis and mossy fibre sprouting.

Kainic acid is a neurotoxin, that has been used for decades to experimentally induce epileptic seizures. Kainic acid is known to cause electrophysiological and morphological changes in rodent brains. These changes are also typical in human epilepsies. Kainic acid can be utilized in in vivo, in vitro and ex vivo. In vitro and ex vivo models have become more and more prominent models to replace whole-animal experiments.

This thesis is a literature review. The goal is to introduce the most essential animal-based in vitro and ex vivo models that have utilized kainic acid to model epileptic seizures. These models include rodent primary neurons, acute hippocampal slices and organotypic hippocampal slices. This thesis focuses on the previous studies done with these models and their main findings. The biological basis and the relevance of glutamatergic signalling to epilepsy is also introduced, in addition to ways of provoking epileptic seizures and ways to measure the electrophysiological activity of cells and tissues.

The thesis concludes that organotypic slice cultures appear to be the most relevant model as it enables long-term surveillance of the slices after kainic acid exposure. Vice versa, rodent primary neurons have not been widely used with kainic acid to study electrophysiological properties, since epilepsy is a property of a complex neural network rather than individual cells. Based on these models, it was also noted that kainic acid-induced seizures target specifically the hippocampus and cause morphological and electrophysiological changes to it. Overall, animal- based in vitro and ex vivo models offer more insight to molecular and network level properties of brain tissue, compared to whole-animal models.