Prototypic Seizure Activity Driven by Mature Hippocampal Fast-Spiking Interneurons

Abstract

A variety of epileptic seizure models have shown that activation of glutamatergic pyramidal cells is usually required for rhythm generation and/or synchronization in hippocampal seizure-like oscillations in vitro. However, it still remains unclear whether GABAergic interneurons may be able to drive the seizure-like oscillations without glutamatergic transmission. Here, we found that electrical stimulation in rat hippocampal CA1 slices induced a putative prototype of seizure-like oscillations ("prototypic afterdischarge," 1.8 -3.8 Hz) in mature pyramidal cells and interneurons in the presence of ionotropic glutamate receptor antagonists. The prototypic afterdischarge was abolished by GABA A receptor antagonists or gap junction blockers, but not by a metabotropic glutamate receptor antagonist or a GABA B receptor antagonist. Gramicidin-perforated patch-clamp and voltage-clamp recordings revealed that pyramidal cells were depolarized and frequently excited directly through excitatory GABAergic transmissions in each cycle of the prototypic afterdischarge. Interneurons that were actively spiking during the prototypic afterdischarge were mostly fast-spiking (FS) interneurons located in the strata oriens and pyramidale. Morphologically, these interneurons that might be "potential seizure drivers" included basket, chandelier, and bistratified cells. Furthermore, they received direct excitatory GABAergic input during the prototypic afterdischarge. The O-LM cells and most of the interneurons in the strata radiatum and lacunosum moleculare were not essential for the generation of prototypic afterdischarge. The GABA-mediated prototypic afterdischarge was observed later than the third postnatal week in the rat hippocampus. Our results suggest that an FS interneuron network alone can drive the prototypic form of electrically induced seizure-like oscillations through their excitatory GABAergic transmissions and presumably through gap junction-mediated communications.

Adenosine Release during Seizures Attenuates GABAAReceptor-Mediated Depolarization

“…This is consistent with earlier evidence that adenosine acts mainly as a seizure-suppressing substance (During and Spencer, 1992;Dunwiddie, 1999;Boison, 2006 (Isomura et al, 2008;Wright et al, 2011) that is often followed by a transient increase in extracellular potassium (Kaila et al, 1997;Viitanen et al, 2010). This rapid depolarizing shift in E GABAA can create a situation where GABA A R activity excites pyramidal cells and thus actually promotes their activity further (Köhling et al, 2000;Fujiwara-Tsukamoto et al, 2010). Our gramicidin recordings enabled us to record GABA A R-mediated signals without disturbing intracellular chloride concentration dynamics during seizure episodes.…”

“…The result is a collapse in the trans-membrane Cl Ϫ gradient and pronounced depolarizing shift in the reversal potential of the GABA A R (E GABAA ) Staley et al, 1995;Kaila et al, 1997). This depolarizing shift in E GABAA is thought to establish the conditions for networks of GABAergic neurons to generate synchronized after-discharges that are char-acteristic of epileptiform activity (Michelson and Wong, 1991;Fujiwara-Tsukamoto et al, 2010).…”

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.…”

“…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. 2A) (Gnatkovsky et al 2008).…”

Regulation of epileptiform discharges in rat neocortex by HCN channels

“…This produces inhibition that modulates network activity in diverse ways, including regulating the firing probability of target cells (Miles et al 1996), synchronizing neuronal activity (Cobb et al 1995), and tuning synaptic integration (Pouille and Scanziani 2001). Fast-spiking (FS) interneurons can drive electrically induced seizurelike oscillations in the hippocampus (Fujiwara-Tsukamoto et al 2010). Although immunoreactivity for HCN channels is not prominent in many neocortical GABAergic interneurons (Lorincz et al 2002), it has been observed in hippocampal interneurons (Lorincz et al 2002) along with HCN mRNA (Brewster et al 2007).…”