Mechanisms of Epileptiform Synchronization in Cortical Neuronal Networks

Abstract

Neuronal synchronization supports different physiological states such as cognitive functions and sleep, and it is mirrored by identifiable EEG patterns ranging from gamma to delta oscillations. However, excessive neuronal synchronization is often the hallmark of epileptic activity in both generalized and partial epileptic disorders. Here, I will review the synchronizing mechanisms involved in generating epileptiform activity in the limbic system, which is closely involved in the pathophysiogenesis of temporal lobe epilepsy (TLE). TLE is often associated to a typical pattern of brain damage known as mesial temporal sclerosis, and it is one of the most refractory adult form of partial epilepsy. This epileptic disorder can be reproduced in animals by topical or systemic injection of pilocarpine or kainic acid, or by repetitive electrical stimulation; these procedures induce an initial status epilepticus and cause 1-4 weeks later a chronic condition of recurrent limbic seizures. Remarkably, a similar, seizure-free, latent period can be identified in TLE patients who suffered an initial insult in childhood and develop partial seizures in adolescence or early adulthood. Specifically, I will focus here on the neuronal mechanisms underlying three abnormal types of neuronal synchronization seen in both TLE patients and animal models mimicking this disorder: (i) interictal spikes; (ii) high frequency oscillations (80-500 Hz); and (iii) ictal (i.e., seizure) discharges. In addition, I will discuss the relationship between interictal spikes and ictal activity as well as recent evidence suggesting that specific seizure onsets in the pilocarpine model of TLE are characterized by distinctive patterns of spiking (also termed preictal) and high frequency oscillations.

Physiological maturation and drug responses of human induced pluripotent stem cell-derived cortical neuronal networks in long-term culture

“…Predictable and stable responses are important for the standardization of drug screening using the MEA system. Kainic acid, which is known to cause convulsions in cerebral cortex slices in vitro 29 30 31 32 , evoked a large increase in spontaneous SBF number, particularly at 33–36 WIV. Thus, these networks mirrored the response of cortical slices.…”

Epileptiform synchronization and high-frequency oscillations in brain slices comprising piriform and entorhinal cortices

“…Excessive neuronal synchronization is, however, the hallmark of epileptic discharges recorded in the EEG of both patients and animal models, and includes interictal and ictal activity along with high-frequency oscillations (HFOs, 80-500 Hz) (Avoli and de Curtis, 2011;Jefferys et al, 2012). Cellular, pharmacological and molecular studies performed over the last few decades have led to remarkable progresses in identifying the mechanisms underlying epileptiform synchronization (Noebels et al, 2012), and much of this evidence was obtained by employing in vitro brain slices comprising the hippocampus proper and parahippocampal structures such as the entorhinal cortex (EC) or the amygdala (Avoli and de Curtis, 2011;Avoli, 2014); these areas belong to the limbic system that is closely involved in the pathophysiogenesis of mesial temporal lobe epilepsy (Gloor, 1997).…”

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

“…4-AP blocks transient K + currents, prolonging action potentials by inhibiting repolarization. As this can act on both glutamatergic and GABAergic neurons, the release of GABA is reduced, leading to excitation ( Avoli, 2014 ).…”