“Interneurons and principal cell firing in human limbic areas at focal seizure onset”

Since the discovery of inhibitory post-synaptic potentials (IPSPs) by Sir John Eccles in 1952, and the identification of GABA (gamma-Aminobutyric acid) as the major inhibitory neurotransmitter in the brain by Dr. Krešimir Krnjević in the early 1970s (see for review, Avoli and Krnjević, 2016), it has largely been assumed that synaptic inhibition functionsto arrest or restrain focal seizures (Levy and O’Leary, 1965). Dr. David Prince demonstrated in 1967 that following cortical application of penicillin, neurons exhibited depolarizing shifts during epileptiform discharges at the focus, while neurons surrounding the focus exhibited prominent IPSPs (Prince and Wilder, 1966). This finding lent further credence that synaptic inhibition served to restrain focal seizures. The advent of advanced microelectrode recording techniques in patients (Babb et al., 1987)(Stead et al., 2010)(Truccolo et al., 2011)(Schevon et al., 2012)(Lambrecq et al., 2017)(Misra et al., 2018)(Elahian et al., 2018) has only recently provided a means to test the validity of this assumption with respect to spontaneous seizures in epileptic patients. Microelectrode recordings are extracellular and cannot be used to distinguish excitatory from inhibitory post-synaptic activity. However, single unit analysis of action potentials in the local field potentials (LFPs) recorded by microelectrodes can be used to distinguish excitatory principal neuron firing from interneuron firing on the basis of morphology (Elahian et al., 2018). Unfortunately, consensus has not been reached by investigators with respect to the role of synaptic inhibition in human seizure genesis and spread. While some teams of investigators have promoted the classical interpretation that synaptic inhibition functions to restrict and perhaps stop the spread of focal seizures (Schevon et al., 2012), others have suggested that inhibition may actually promote the initiation and the spread of seizure activity (Elahian et al., 2018). The role of synaptic inhibition in seizure genesis and spread is undoubtedly complex, and the mechanisms responsible are unlikely monolithic. For instance, the morphology of seizure onset patterns are not homogeneous (Perucca et al., 2014), and each pattern may reflect distinct cellular and network events. In the human neocortex, the most common seizure onset pattern is called low-voltage fast (LVF) and consists of beta-(15–30 Hz) or gamma (30–80 Hz) EEG activity with an amplitude typically less than 80μV (Gnatkovsky et al., 2014; Perucca et al., 2014; de Curtis and Gnatkovsky., 2009). In contrast, in patients with mesial temporal lobe epilepsy exclusively, the hypersynchronous (HYP) pattern is seen most frequently and consists of evolving repetitive sharply contoured high-amplitudeictal discharges at a frequency of 0.5–2 Hz (Velasco et al., 2000; Devinsky et al., 2018). Adding to the complexity is the fact that one seizure onset pattern can sometimes evolve into another pattern (Weiss et al., 2016). Also, in restricted cortical microcolumns, microseizures in the local field potential with HYP-like morphology can precede the EEG seizure onset pattern recorded from the clinical macroelectrode (Stead et al., 2010; Weiss et al., 2016). Thus, to properly dissect out the role of synaptic inhibition in seizure genesis and spread it is important to implement, at the very least, a taxonomic approach based on seizure onset morphologies (Perucca et al., 2014). With respect to the role of synaptic inhibition in LVF onset seizures, several unique and complementary approaches have yielded important clues for investigators. This review focuses on how the role of synaptic inhibition in the LVF onset pattern contrasts with its role in the HYP onset pattern in humans. We will examine results from human studies performed with microelectrode recordings of LVF onset seizures, by doing so, we will consider this evidence within the context of several studies that have been obtained from animal models of mesial-temporal lobe and neocortical epilepsy. Few human microelectrode studies have differentiated LVF onset seizures from other EEG seizure onset types (Elahian et al., 2018) (Lambrecq et al., 2017)(Weiss et al., 2016). In contrast, most studies utilizing animal models have carefully distinguished LVF from other seizure onset types (see: Lévesque et al., 2012; Bragin et al., 2005; Bragin et al., 1999). An important early clue that inhibition may promote seizure genesis was found in acute brain slices treated with 4-amonopyridine (4-AP). In this preparation, bath application of glutamate receptor antagonists revealed a depolarizing GABAergic potential that occurred during seizure discharges that contained LVF-like features (Avoli et al., 1993; Avoli et al., 1996). Building on this unexpected finding, in vivo microelectrode recording (Karunakaran et al., 2016)(Grasse et al., 2013), and in vitro intra-(Uva et al., 2015)(Ziburkus et al., 2006) (Gnatkovsky et al., 2008)(Lopantsev and Avoli, 1998) and extra-(Lévesque et al., 2016) (Lévesque et al., 2012) cellular recordings confirmed that LVF activity begins with the increased firing of inhibitory interneurons. Most recently, optogenetic stdies have demonstrated that LVF seizures can even be elicited in acute slices by optogenetically stimulating different types of inhibitory interneurons(Chang et al., 2018)(Shiri et al., 2016) (Shiri et al., 2015)(Yekhlef et al., 2015). Finally, modeling studies have been used to further investigate how the increased firing rate of inhibitory interneurons could potentially trigger seizure genesis and/or spread (Ho and Truccolo, 2016).