Epileptogenesis in organotypic hippocampal cultures has limited dependence on culture medium composition

Liu, Jing; Saponjian, Yero; Mahoney, Mark M.; Staley, Kevin J.; Berdichevsky, Yevgeny

doi:10.1371/journal.pone.0172677

Cited by 22 publications

(28 citation statements)

References 70 publications

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“…Only in the case of in vitro brain slices can the dynamics of a single node be observed. It has been reported that such slices will produce spontaneous epileptiform activity . The node dynamics can be made more sophisticated and realistic by using physiologically detailed neural mass models, which have been designed to describe a variety of activities as observed in EEG signals …”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that such slices will produce spontaneous epileptiform activity. 12,13 The node dynamics can be made more sophisticated and realistic by using physiologically detailed neural mass models, which have been designed to describe a variety of activities as observed in EEG signals. 14 A promising development is to tailor this approach to individual patients, for example, those undergoing chronic invasive EEG monitoring, by using a patient-specific network model.…”

Section: Discussionmentioning

confidence: 99%

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Phenomenological network models: Lessons for epilepsy surgery

et al. 2017

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SUMMARYThe current opinion in epilepsy surgery is that successful surgery is about removing pathological cortex in the anatomic sense. This contrasts with recent developments in epilepsy research, where epilepsy is seen as a network disease. Computational models offer a framework to investigate the influence of networks, as well as local tissue properties, and to explore alternative resection strategies. Here we study, using such a model, the influence of connections on seizures and how this might change our traditional views of epilepsy surgery. We use a simple network model consisting of four interconnected neuronal populations. One of these populations can be made hyperexcitable, modeling a pathological region of cortex. Using model simulations, the effect of surgery on the seizure rate is studied. We find that removal of the hyperexcitable population is, in most cases, not the best approach to reduce the seizure rate. Removal of normal populations located at a crucial spot in the network, the "driver," is typically more effective in reducing seizure rate. This work strengthens the idea that network structure and connections may be more important than localizing the pathological node. This can explain why lesionectomy may not always be sufficient.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phenomenological network models: Lessons for epilepsy surgery

et al. 2017

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“…Compared with acute slices, OS require more time and resources, particularly a culture medium which can provide essential growth factors, hormones and metabolites; which may or may not include serum. As variability between culture media can frequently be attributed to serum, chemically defined media have also been developed and have been shown to support OS culture and more importantly facilitate seizurogenesis ( Liu et al, 2017 ).…”

Section: Current In Vitro Models Of Seizurementioning

confidence: 99%

In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells

et al. 2018

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The brain is the most complex organ in the body, controlling our highest functions, as well as regulating myriad processes which incorporate the entire physiological system. The effects of prospective therapeutic entities on the brain and central nervous system (CNS) may potentially cause significant injury, hence, CNS toxicity testing forms part of the “core battery” of safety pharmacology studies. Drug-induced seizure is a major reason for compound attrition during drug development. Currently, the rat ex vivo hippocampal slice assay is the standard option for seizure-liability studies, followed by primary rodent cultures. These models can respond to diverse agents and predict seizure outcome, yet controversy over the relevance, efficacy, and cost of these animal-based methods has led to interest in the development of human-derived models. Existing platforms often utilize rodents, and so lack human receptors and other drug targets, which may produce misleading data, with difficulties in inter-species extrapolation. Current electrophysiological approaches are typically used in a low-throughput capacity and network function may be overlooked. Human-derived induced pluripotent stem cells (iPSCs) are a promising avenue for neurotoxicity testing, increasingly utilized in drug screening and disease modeling. Furthermore, the combination of iPSC-derived models with functional techniques such as multi-electrode array (MEA) analysis can provide information on neuronal network function, with increased sensitivity to neurotoxic effects which disrupt different pathways. The use of an in vitro human iPSC-derived neural model for neurotoxicity studies, combined with high-throughput techniques such as MEA recordings, could be a suitable addition to existing pre-clinical seizure-liability testing strategies.

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“…Organotypic cultures must be prepared from very young animals, and the development of epileptiform activity may be sensitive to variations in culture conditions. Recent reports, however, mitigate concerns regarding culture media . Caveats of using organotypic slice culture include cell death, glial proliferation, and slicing‐ and culture‐induced network reorganization.…”

Section: General Categories Of Models and Their Benefits/limitationsmentioning

confidence: 99%

How do we use in vitro models to understand epileptiform and ictal activity? A report of the TASK1‐WG4 group of the ILAE/AES Joint Translational Task Force

et al. 2018

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SummaryIn vitro brain tissue preparations allow the convenient and affordable study of brain networks and have allowed us to garner molecular, cellular, and electrophysiologic insights into brain function with a detail not achievable in vivo. Preparations from both rodent and human postsurgical tissue have been utilized to generate in vitro electrical activity similar to electrographic activity seen in patients with epilepsy. A great deal of knowledge about how brain networks generate various forms of epileptiform activity has been gained, but due to the multiple in vitro models and manipulations used, there is a need for a standardization across studies. Here, we describe epileptiform patterns generated using in vitro brain preparations, focusing on issues and best practices pertaining to recording, reporting, and interpretation of the electrophysiologic patterns observed. We also discuss criteria for defining in vitro seizure‐like patterns (i.e., ictal) and interictal discharges. Unifying terminologies and definitions are proposed. We suggest a set of best practices for reporting in vitro studies to favor both efficient across‐lab comparisons and translation to in vivo models and human studies.

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Epileptogenesis in organotypic hippocampal cultures has limited dependence on culture medium composition

Cited by 22 publications

References 70 publications

Phenomenological network models: Lessons for epilepsy surgery

Phenomenological network models: Lessons for epilepsy surgery

In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells

How do we use in vitro models to understand epileptiform and ictal activity? A report of the TASK1‐WG4 group of the ILAE/AES Joint Translational Task Force

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