Understanding the role of the piriform cortex in epilepsy
Creators: name: Robertson, Jennifer
Publisher: name: The Australian National University
Year: 2019

description: The piriform cortex is the first site of cortical odour processing. Curiously, it is also involved in epilepsy. Epilepsy is a debilitating condition characterised by multiple seizures, which affects over 65 million people worldwide. Despite decades of research, current epilepsy treatments are ineffective in more than 30% of sufferers. Early studies demonstrated that seizures could generate more rapidly in the piriform cortex than in any other part of the brain, and recent human studies show focal seizures propagate through the piriform cortex, regardless of origin. Clearly, the piriform cortex is important for epilepsy. Unfortunately, understanding of its role in epilepsy is in its infancy. This thesis contributes to our understanding on three levels. First, to understand the pathological role of the piriform cortex, it is important to understand its normal structure and function. Previous research in our laboratory rigorously characterised the excitatory neurons in layer 2 and the inhibitory neurons in all layers. However, the excitatory neurons in layer 3 remained largely unexamined. These neurons are particularly important for epilepsy as they are located in the part of the piriform cortex where seizures initiate most easily. We recorded the morphology, electrophysiology and synaptic connectivity of 59 excitatory neurons in layer 3. By employing a rigorous approach to cluster analysis, we identified two distinct classes of excitatory neurons in layer 3 and quantified the differences in their properties. By completing the classification of its neurons, we are now better equipped to study the normal and pathological functioning of the piriform cortex. Second, because epilepsy is a network phenomenon, it is important to understand how groups of neurons in the piriform cortex behave during seizure activity. Here, we utilised several different in vitro epilepsy models and recording techniques to investigate activity in the piriform cortex under hyperexcitable conditions. We found that the neurons in the piriform cortex exhibited asynchronous spontaneous epileptiform bursts after application of proconvulsant solutions. However, after an electrical stimulus to layer 3, these neurons abruptly switched to a synchronous firing mode. Pharmacological experiments implicated the involvement of NMDA receptors, AMPA receptors and voltage-gated sodium channels in this mode-switch. We propose this change in synchrony may be a mechanism by which the piriform cortex becomes 'primed' for epileptic seizure propagation. Third, we investigated long-term changes to the epileptic piriform cortex. Inhibitory neurons have a particularly important, albeit complex role in epilepsy. Some inhibitory neuronal cell types promote seizure propagation, while others oppose it. Using an electrical kindling model, we compared the density of different inhibitory neuronal cell types in epileptic and non-epileptic mice. Our results show a reduction in density of inhibitory neurons that may suppress seizures and a relative increase in density of inhibitory neurons that may promote seizures. We propose that these changes may be another mechanism by which the piriform cortex facilitates seizure propagation. In conclusion, this thesis provides insight into mechanisms by which the piriform cortex may promote seizure propagation. Future studies will further elucidate the mechanisms and may lead to the development of novel epilepsy treatments targeting the piriform cortex.