Models of drug-induced epileptiform synchronization in vitro

Abstract

Models of epileptiform activity in vitro have many advantages for recording and experimental manipulation. Neural tissues can be maintained in vitro for hours, and in neuronal or organotypic slice cultures for several weeks. A variety of drugs and other agents increase activity in these in vitro conditions, in many cases resulting in epileptiform activity, thus providing a direct model of symptomatic seizures. We review these preparations and the experimental manipulations used to induce epileptiform activity. The most common of drugs used are GABA A receptor antagonists and potassium channel blockers (notably 4-aminopyridine). Muscarinic agents also can induce epileptiform synchronization in vitro, and include potassium channel inhibition amongst their cellular actions. Manipulations of extracellular ions are reviewed in another paper in this special issue, as are ex vivo slices prepared from chronically epileptic animals and from people with epilepsy. More complex slices including extensive networks and/or several connected brain structures can provide insights into the dynamics of long range connections during epileptic activity. Visualization of slices also provides opportunities for identification of living neurons and for optical recording/stimulation and manipulation. Overall, the analysis of the epileptiform activity induced in brain tissue in vitro has played a major role in advancing our understanding of the cellular and network mechanisms of epileptiform synchronization, and it is expected to continue to do so in future.

Paroxysmal Discharges in Tissue Slices From Pediatric Epilepsy Surgery Patients: Critical Role of GABAB Receptors in the Generation of Ictal Activity

“…Also, cytomegalic interneurons in cases of severe cortical dysplasia (CD), i.e., CD type II, may generate spontaneous paroxysmal depolarizations (Andre et al, 2007). In order to induce paroxysmal discharges in tissue slices, the ionic concentrations of the bathing solution have been manipulated (e.g., Mg 2+ removal or increased K + concentration), or proconvulsant agents such as GABA A receptor antagonists (bicuculline, BIC, or picrotoxin) and K + -channel blockers [4-aminopyridine (4-AP)] have been used (Avoli et al, 1999(Avoli et al, , 2003D'Antuono et al, 2004;Avoli and Jefferys, 2016). Of particular interest is the fact that human CD tissue is exquisitely sensitive to the proconvulsant effects of 4-AP, as this drug induces spontaneous seizures in about 50% of slices from CD, but not from mesial temporal lobe epilepsy cases (Avoli et al, 1999;D'Antuono et al, 2004).…”

Human cerebral tissues created via active cellular reaggregation produce functionally interconnected 3D neuronal network to mimic pathological circuit disturbance

“…Therefore, the combination of cerebral tissue formation using MARC and this interacting separated 3D coculture (iS3CC) chip is ideally suited for investigations into the signal transmission between interconnected cerebral tissue cultures. A-receptor (GABAAR) blocker of the β-lactam antibiotics family 24 . The epileptiform mechanism of Penicillin G has been theoretically and experimentally shown to occur through the specific binding of Penicillin G with GABAAR in an open configuration, which prevents GABAergic transmission in CNS 25 and results in a hypersynchronous activity in the brain due to interference of the GABA-inhibition and glutamate-excitation equilibrium, causing abnormal electrical discharges 26 .…”

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

“…In vitro models are mainly models of epileptogenesis, such as organotypic brain slices, or models of epileptiform activity, in which the biological preparations, like neuronal cultures or acute brain slices, are susceptible to chemoconvulsants, and therefore, epileptiform activity is acutely induced (reviewed in Reference [ 41 ]).…”