Transition to Seizure: Ictal Discharge Is Preceded by Exhausted Presynaptic GABA Release in the Hippocampal CA3 Region

Abstract

How the brain transitions into a seizure is poorly understood. Recurrent seizure-like events (SLEs) in low-Mg 2ϩ /high-K ϩ perfusate were measured in the CA3 region of the intact mouse hippocampus. The SLE was divided into a "preictal phase," which abruptly turns into a higher frequency "ictal" phase. Blockade of GABA A receptors shortened the preictal phase, abolished interictal bursts, and attenuated the slow preictal depolarization, with no effect on the ictal duration, whereas SLEs were blocked by glutamate receptor blockade. In CA3 pyramidal cells and stratum oriens non-fast-spiking and fast-spiking interneurons, recurrent GABAergic IPSCs predominated interictally and during the early preictal phase, synchronous with extracellularly measured recurrent field potentials (FPs). These IPSCs then decreased to zero or reversed polarity by the onset of the higher-frequency ictus. However, postsynaptic muscimol-evoked GABA A responses remained intact. Simultaneously, EPSCs synchronous with the FPs markedly increased to a maximum at the ictal onset. The reversal potential of the compound postsynaptic currents (combined simultaneous EPSCs and IPSCs) became markedly depolarized during the preictal phase, whereas the muscimol-evoked GABA A reversal potential remained unchanged. During the late preictal phase, interneuronal excitability was high, but IPSCs, evoked by local stimulation, or osmotically by hypertonic sucrose application, were diminished, disappearing at the ictal onset. We conclude that the interictal and early preictal states are dominated by GABAergic activity, with the onset of the ictus heralded by exhaustion of presynaptic release of GABA, and unopposed increased glutamatergic responses.

Initiation, Propagation, and Termination of Partial (Focal) Seizures

“…Low-voltage fast activity and hypersynchronous onset patterns can also be reproduced in a combined hippocampus-entorhinal cortex, or hippocampus amygdala slices perfused in vitro with either 4AP (Lopantsev and Avoli 1998;Avoli et al 2013b), low-magnesium and highpotassium solution (Derchansky et al 2006;Zhang et al 2012), as well as following highfrequency tetanic stimulation (Isomura et al 2008;Fujiwara-Tsukamoto et al 2010). In these in vitro models, low-voltage fast activity onset is characterized at the start by a prominent activation of inhibitory interneurons (Velazquez and Carlen 1999;Kohling et al 2000;Ziburkus et al 2006;Lasztoczi et al 2009;Fujiwara-Tsukamoto et al 2010), which transiently shut off principal cells ( Fig.…”

“…Both low-voltage fast activity and hypersynchronous seizure-onset patterns are typically observed in animal models of mesial TLE (Engel et al 1990;Bragin et al 1999;Levesque et al 2012) and in models of acute temporal seizures (Bragin et al 1999;Zhang et al 2012;Levesque et al 2013;Boido et al 2014a). These two patterns may be the expression of the activation of the same networks, because the large-amplitude spikes typically detected in the hypersynchronous pattern are often followed by short runs of low-voltage fast activity (Perucca et al 2014).…”

“…Hypersynchronous pattern at seizure onset is most consistently observed when cortical excitability is enhanced in brain slices by a solution containing low magnesium and high potassium (Derchansky et al 2006;Lasztoczi et al 2009;Zhang et al 2012). In these conditions, a gradual recruitment of both inhibitory and excitatory networks occurs (Derchansky et al 2008).…”

Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention

“…This result is particularly relevant for the interpretation of neuronal rate changes in advance of seizures preceded by REM sleep given that REM sleep has a propensity for preceding seizures in two separate rat models of chronic temporal lobe epilepsy ( 4 and Sedigh-Sarvestani et al, 2014). Several in vitro studies have suggested that increases in interneuron activity would be expected to precede seizures (Trevelyan et al, 2007;Lasztó czi et al, 2009;Zhang et al, 2012;Shiri et al, 2015). When such pre-ictal increases were observed in vivo, they were therefore interpreted to be pathological indicators of oncoming seizures (Bower and Buckmaster, 2008, Grasse et al, 2013, Truccolo et al, 2011.…”

Models of drug-induced epileptiform synchronization in vitro

“…During the last two decades this preparation has been employed in several laboratories for analyzing the generation and spread of epileptiform discharges (Derchansky et al, 2004(Derchansky et al, , 2006(Derchansky et al, , 2008Zhang et al, 2012). Isolated hippocampi in most of these studies had to be obtained from neonatal or very young rats (up to 15 days postnatal) but more recently older animals (up to 22 days postnatal) have been used, even though these experiments have so far addressed the generation of physiological theta rhythms rather than epileptiform synchronization (Gu et al, 2013).…”