Dysregulation of developing neural circuits during epileptogenesis

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New neurons are born throughout life: their generation, integration and function are tightly regulated. Impairment of this process is associated with brain circuit dysfunction and the development of epileptiform activity and sensory hypersensitivity, associated with neurodevelopmental disorders. In several models of epileptogenesis, prior and repeated seizure activity (e.g. from traumatic brain injury) results in increased seizure susceptibility and eventually epilepsy. Neurogenesis is known to be disrupted following repeated seizure activity, which can alter cell proliferation, survival, differentiation and functional maturation of new neurons as they incorporate into existing neural circuits. Since altered neurogenesis has been shown to be a causative factor in both spreading depression and seizure generation, both pathophysiological hallmarks of epilepsy, it is important to understand whether abnormal circuit activity and perturbed neurogenesis cause newborn neurons to improperly integrate and function within existing brain circuits, disturbing activity and leading to epilepsy. This proposal tests the hypothesis that seizure activity and network hyperexcitability perturb development and function of new neurons, resulting in highly excitable neurons that potentiate network hyperexcitability and lead to epilepsy and sensory hypersensitivity. We will a reduced preparation, the Xenopus laevis tadpole tectum—an established model for studying generation of new neurons and the biological basis for epilepsy. It is a highly recurrent structure with ongoing integration of new neurons, and thus ideally placed for understanding the fundamental biological underpinnings of developmental epilepsy. We will use genetic methods to tag later-born neurons and follow them in vivo as they integrate into existing brain circuits following developmental seizure exposure. We will measure the structure and physiology of these neurons as they mature. We will then test whether we can manipulate the electrical activity of these miswired neurons and test whether we can ameliorate seizure activity. Finally, we will examine genes that are expressed incorrectly in later born neurons following a seizure to test whether these genetic pathways can be responsible for the abnormal development of these neurons and miswiring of the brain following a seizure. Improving our understanding of how exposure to prior seizures affects the maturation of neural circuits, and how this in turn leads to epilepsy will not only help illustrate the basic biology underlying epileptogenesis, but will result in potential therapeutic targets that could prevent formation of epilepsy following a series of seizures, such as those experienced after brain injury.