Epilepsy in a dish: an in vitro model of epileptogenesis.

Commentary Animal models of epilepsy have helped to promote investigations of underlying mechanisms of epileptogenesis and to facilitate the development and screening of novel treatments. A large number and variety of animal models have been created, the equally numerous types and causes of epilepsy in people. Of course, in vivo models of epilepsy, in which animals exhibit actual behavioral and electroencephalographic seizures, most closely mimic the clinical features of human epilepsy. However, reduced biological systems, including brain slices, cell culture, and molecular assays, may also be advantageous in offering unique mechanistic insights into epilepsy. As there is obviously no perfect animal model of epilepsy, ultimately each model system must be carefully evaluated for its specific advantages and limitations in studying different aspects of epilepsy. Given the complexity of epilepsy, there is increasing interest in developing simplified in vitro models of epilepsy that allow more detailed investigations of cellular and molecular mechanisms of epileptogenesis while still preserving the critical network phenotypic features of epilepsy, particularly the development of spontaneous seizures. Intact hippo-campal preparations or acute brain slices maintain much of the needed circuitry to generate electrographic seizures (1, 2). However, these preparations are typically only viable for several hours and thus are primarily useful only for studying acutely provoked seizures, not chronic epileptogenesis. Or-ganotypic slice cultures, which can be maintained for weeks or longer, have been used to study a number of physiological and pathological processes in the brain, including circuit development , synaptic plasticity, and axonal sprouting (3). Slice cultures also afford the opportunity to investigate epilepsy. Most previous studies of organotypic slice cultures have focused on interictal spikes and electrographic seizures acutely provoked by convulsant drugs or other pharmacologic conditions over a relatively short time course (4–6). However, some studies have examined the development of spontaneous epileptiform activity over several weeks, which more closely mimics the process of epileptogenesis that occurs with in vivo animal models and human epilepsy (7, 8). The recent study by Dyhrfjeld-Johnsen et al. provides perhaps the most detailed characterization to date of the development and evolution of epileptiform activity within a chronic, In organotypic hippocampal slice cultures, principal neurons form aberrant excitatory connections with other principal cells in response to slicing induced deafferentation, similar to mechanisms underlying epileptogenesis in posttraumatic epilepsy. To investigate the consequences of this synaptogenesis, the authors recorded field-potential activity from area CA3 during perfusion with the complete growth medium used …