Abstract

The mechanisms underlying the generation of interictal spikes identified in the electroencephalograms of epileptic patients and animal models of focal epilepsy have become more and more defined as technical advances in the analysis of these events have evolved. Central to this chapter, several investigators have focused on the paroxysmal depolarizing shift (PDS), which is thought to be the intracellular counterpart of the interictal spike generated by neuronal networks and intrinsic membrane conductances in both in vivo and in vitro preparations that mimic focal epileptic disorders. Here, we will review early in vivo experiments, in which the PDS was first identified, as well as later in vitro studies that were performed during GABA_A receptor antagonism but also during concomitant enhancement of excitatory and inhibitory synaptic mechanisms. Finally, we will review the contribution of intrinsic neuronal mechanisms, and in particular dendritic Ca²⁺ action potentials, to the generation of the PDS. The findings reviewed here outline some concepts on brain function that have emerged by analyzing the generation of the PDS during the last six decades, and that may play a role in other pathological, and perhaps even physiological, activities.

Introduction

The paroxysmal depolarizing shift (PDS), a large-amplitude depolarization associated with action potential bursting, has been considered to represent the cellular counterpart of the interictal spike that occurs between seizures in the electroencephalograms (EEGs) recorded from patients presenting with focal epileptic disorders. Interictal spikes usually consist of a large-amplitude, rapid component followed by a slow wave and are employed in clinical practice to localize the seizure-onset zone in focal epileptic disorders (de Curtis et al., 2012; de Curtis & Avanzini, 2001), a procedure fundamental for performing successful surgical interventions in patients with focal epilepsy not responding to pharmacological therapy.

The PDS was the first epileptiform event to be identified at the cellular level in cortical “epileptic” foci that were acutely induced by topical application of convulsive agents. This landmark study, which reported large-amplitude neuronal depolarizations associated with action potential burst firing occurring during EEG epileptiform spikes in a neocortical area treated with strychnine, was authored by Chu Lu Li (Li, 1959). Dr. Li was a past fellow in Dr. H. H. Jasper’s laboratory at the Montreal Neurological Institute, who was at that time working at the National Institutes of Health. During the following years, experimental work from different laboratories confirmed that shortly after an acute, topical application of penicillin or a cortical freeze lesion, the treated neocortical area became an “epileptic focus” generating interictal spikes that were associated with intracellularly recorded PDSs (Goldensohn & Purpura, 1963; Matsumoto & Ajmone Marsan, 1964; Prince, 1967, 1968a, 1968b) (Fig. 1–1A). A similar association between the interictal spike and PDS was also identified in penicillin-induced acute hippocampal foci (Dichter & Spencer, 1969b, 1969a) and in epileptic foci of the chronic alumina cream model in primates (Prince & Futamachi, 1970) (Fig. 1–1B).

Figure 1–1.

PDSs and associated field potential events recorded in vivo and in vitro preparations. A. EEG (upper trace) and intracellular (lower trace) recordings obtained from an epileptogenic focus made in the pericruciate cortex by pial application of penicillin. (more...)

These early studies were carried out in vivo, but the introduction of in vitro brain slice preparations and the demonstration that the PDS could be reproduced in isolated brain networks (Fig. 1–1C) (Schwartzkroin & Andersen, 1975) allowed for increasingly detailed inquiries into the fundamental mechanisms that cause its generation. This chapter summarizes the findings obtained during the last six decades on this topic and focuses on their relevance for possible future experiments.

Neuronal Networks, Synaptic and Intrinsic Membrane Currents, and PDS Generation

Much research and debate during the late 1960s and early 1970s revolved around the question of the relative contributions of intrinsic membrane and synaptic currents to the PDS in single neurons, and thus to the focal interictal population spike observed in acute models of epileptiform synchronization. Johnston and Brown (1981), employing recently developed single-electrode voltage clamp recordings, reported that the PDS generated by CA3 pyramidal cells during application of the GABA_A receptor antagonist bicuculline behaves as expected for a network-driven, giant synaptic excitatory potential. Similar conclusions were drawn from analyzing PDSs in experiments performed in neocortical slices that were treated with bicuculline (Gutnick et al., 1982). Wong and colleagues also showed that single hippocampal pyramidal cells could initiate synchronous epileptiform events in a population of interconnected neurons after blockade of synaptic inhibition in slices (Traub et al., 1984; Wong et al., 1986). It should be emphasized that these early in vitro studies were carried out employing drugs (e.g., penicillin or bicuculline) that antagonize GABA_A receptors (Fig. 1–1D) (Dingledine & Gjerstad, 1979, 1980; Schwartzkroin & Prince, 1978, 1980). Therefore, these experiments demonstrated that PDS generation results from blockade of inhibition (i.e., IPSP), which in turn produces enhanced glutamatergic ionotropic excitation. Accordingly, successive studies have reported that specific ionotropic glutamatergic receptor antagonists decrease the duration or abolish the PDS induced by GABA_A receptor blockers in cortical networks (Fig. 1–1E) (Hwa & Avoli, 1991; Jones, 1988; Lee & Hablitz, 1991).

An important characteristic of the interictal spikes (and thus of the PDSs) recorded from hippocampal slices during GABA_A receptor antagonism rests on the ability of CA3 pyramidal cells to initiate these paroxysmal events, which then spread to the CA1 subfield thus entraining local principal cells in the epileptiform discharge (Fig. 1–1F) (Schwartzkroin & Prince, 1978). In line with this finding, when the Schaffer collaterals were surgically cut, spontaneous epileptiform spikes, which are the field potential counterparts of the PDS—disappeared in the CA1 while persisting in the CA3 subfield (Fig. 1–1G) (Schwartzkroin & Prince, 1978). Further studies have shown that the unique ability of CA3 networks to initiate the PDS rests on the prominent excitatory connectivity that characterizes this hippocampal area (Miles & Wong, 1987, 1983) along with the ability of CA3 pyramidal cells to generate intrinsic, dendritic burst firing (Wong et al., 1979; Wong & Prince, 1978, 1979). The latter feature was originally reported by Kandel and Spencer (1961) during intracellular recordings obtained in vivo from the hippocampus under control conditions.

Interictal spikes are also recorded in vitro following experimental procedures that, in principle, should not interfere with GABAergic inhibition. For instance, when brain slices are bathed in medium containing low Mg²⁺, spontaneous or stimulus-induced interictal spikes associated with PDSs occur in the CA3 and CA1 subfields (Mody et al., 1987; Tancredi et al., 1990). As illustrated in Figure 1–2A, under these experimental conditions, the ability of a CA1 pyramidal cell to generate a PDS in response to orthodromic stimulation of the stratum radiatum coincides with a hyperpolarizing IPSP when the alveus is stimulated. However, the in vitro model of epileptiform synchronization evoked in the absence of decreased inhibition that has provided much information on interictal spiking is the K⁺ channel blocker 4-aminopyridine (4AP) model (Perreault & Avoli, 1991; Rutecki et al., 1987; Voskuyl & Albus, 1985). As illustrated in Figure 1–2B (top panel), application of 4AP to hippocampal slices induces two types of interictal spikes. The first type consists of frequently occurring, fast, interictal events (arrows) that are driven by the CA3 network and are abolished by non-NMDA glutamatergic receptor antagonists (not shown). The second type is characterized by slow interictal discharges (asterisk) that can be generated independently by the three hippocampal areas when they are surgically separated (Fig. 1–2B, bottom panel), and they continue to propagate in intact hippocampal slices when ionotropic glutamatergic excitatory transmission is blocked (not illustrated). These slow interictal events are abolished by drugs that interfere with GABA_A receptor inhibition (Perreault & Avoli, 1991, 1992).

Figure 1–2.

Further electrophysiological features of PDSs and associated interictal spikes in in vitro and in vivo preparations. A. Superimposed responses to stimuli delivered in stratum radiatum (triangle) and alveus (circle) recorded from a CA1 pyramidal cell (more...)

Intracellular recordings from CA3 pyramidal cells have shown that the fast interictal spikes induced by 4AP are associated with strong cellular depolarization and action potential bursting, thus closely resembling typical PDSs. In contrast, the slow interictal spikes are mirrored by a long-lasting depolarization commonly associated with few action potentials that are often generated ectopically (Fig. 1–2C and D) (Perreault & Avoli, 1991, 1992). It has been also reported that, although abolished by glutamatergic receptor antagonists, the fast interictal spikes induced by 4AP reflect the contribution of inhibitory currents, as suggested by the reversal potential of the PDS analyzed with voltage-clamp recordings (Rutecki et al., 1987). These authors found similar evidence for the PDSs induced in CA3 pyramidal cells bathed in a medium containing high [K⁺] (Rutecki et al., 1985) or the K⁺ channel blocker tetraethylammonium (Rutecki et al., 1990). Taken together, this evidence suggests that PDSs are generated by cortical networks when both excitatory and inhibitory synaptic currents are pharmacologically increased.

Studies have identified 4AP-induced glutamatergic-independent spikes in several brain areas (e.g., neocortex and amygdala, as well as entorhinal, perirhinal, insular, and piriform cortices) both in brain slices and in the isolated guinea pig brain preparation (Avoli & de Curtis, 2011). Moreover, similar slow spikes are induced in the entorhinal cortex by the muscarinic agonist carbachol (Dickson & Alonso, 1997). Finally, spontaneous inhibitory potentials support interictal-like oscillations in the neocortex (Köhling et al., 1998), hippocampus (Schwartzkroin & Haglund, 1986), and subiculum (Cohen et al., 2002) of brain slices obtained from patients undergoing surgery for medically intractable epilepsy.

The participation of multiple, distinct synaptic mechanisms in interictal spike generation and the different patterns of associated action potential firing—as demonstrated in the 4AP in vitro model—is in line with the different shape, polarity, and duration of the interictal spikes occurring in EEG recordings obtained from epileptic patients or chronically epileptic animals. Accordingly, high levels of heterogeneity in the single unit firing associated with interictal spikes have been found in epileptic patients (Keller et al., 2010; Truccolo et al., 2011). It should be emphasized that interictal spikes, characterized by different shapes, may play divergent functional roles in ictogenesis (Avoli et al., 2013) as well as in epileptogenesis (Chauvière et al., 2012).

Intrinsic Neuronal Properties and PDS Generation

It is well established that nonsynaptic mechanisms such as intercellular gap junctions and ephaptic interactions contribute to neuronal network synchronization and thus to epileptiform activity (Dudek et al., 1986; Jefferys, 1995; Mylvaganam et al., 2014; Prince & Connors, 1986; Wong et al., 1986). In addition, neuronal behaviors that mirror intrinsic excitability occur during interictal spikes. As illustrated in Figure 1–2D, the slow interictal spikes induced by 4AP in hippocampal slices are associated with the occurrence of ectopic action potentials in pyramidal cells as suggested by their variable amplitudes, IS-SD fractionation, and their generation at membrane potential values that were more negative than action potential threshold (Avoli et al., 1998; Perreault & Avoli, 1992). In addition, ectopic action potentials have been identified in neocortical interneurons during synchronous GABAergic activity induced by 4AP application (Keros & Hablitz, 2005). Ectopic action potentials during epileptiform spikes were originally recorded in thalamocortical cells whose axons projected to a neocortical penicillin-induced focus (Gutnick & Prince, 1972) (Fig. 1–2E) and in cortical seizures triggered by tetanic stimulation (Noebels & Prince, 1978). These action potentials originated from intracortical axons and propagated, antidromically, back to the thalamic somato-dentritic compartment, but also orthodromically to the excitatory intracortical terminals, where they would provide an additional thalamocortical excitatory drive within the cortical epileptic focus, thus contributing to PDS generation.

Role of Dendritic Ca²⁺ Spikes in PDS Generation

Although early studies concluded that dendritic membranes were unexcitable to direct depolarization (Grundfest & Purpura, 1956), and therefore would not contribute to the slow depolarizing envelope of the PDS, later intra-dendritic recordings in Purkinje cells showed that dendrites can generate slow voltage-dependent Ca²⁺-mediated depolarizations (Llinás & Hess, 1976; Llinas & Nicholson, 1971). Intra-somatic recordings suggested that “probable” Ca²⁺ spikes were generated in hippocampal pyramidal cell dendrites (Schwartzkroin & Slawsky, 1977). Moreover, intra-dendritic recordings in hippocampal CA1 and CA3 pyramidal neurons showed that bursts containing both fast Na⁺ and slower Ca²⁺ spikes could be evoked by synaptic or direct depolarization (Wong et al., 1979; Wong & Prince, 1978, 1979) (Fig. 1–3). Finally, when postsynaptic inhibition was decreased with penicillin, spontaneous and evoked large-amplitude slow bursts of Na⁺ and Ca²⁺ spikes were generated in the dendrites of CA1 pyramidal neurons, coincident with PDSs (Wong et al., 1979; Wong & Prince, 1979) (Fig. 1–3B).

Figure 1–3.

Intradendritic recordings from CA1 pyramidal cells under control conditions and during application of penicillin. A. Under control conditions, injection of a depolarizing pulse triggers an intrinsic burst of action potentials (a) while an EPSP-IPSP sequence (more...)

These results were confirmed and extended in isolated hippocampal pyramidal cell dendrites (Benardo et al., 1982; Masukawa & Prince, 1984). More recent intra-dendritic recordings have also demonstrated that both Na⁺ and Ca²⁺ spikes are generated in neocortical pyramidal neurons (Amitai et al., 1993). Such dendritic depolarizations would contribute to the PDS slow envelope when postsynaptic inhibition is reduced, as reported in many epilepsy models (Houser & Esclapez, 1996; Kumar & Buckmaster, 2006; H. Li & Prince, 2002; Ma & Prince, 2012; Perez-Ramirez et al., 2020; Ribak et al., 1982; Rosen et al., 1998). Dendritic Ca²⁺-mediated depolarizations in a population of pyramidal neurons would increase their synchronous excitatory output and contribute to generation of the PDS in the cortical network.

Dendritic Abnormalities in Models of Epilepsy

The role of dendritic structure and function as well as the contributions of dendritic abnormalities in epileptic disorders was extensively reviewed by Cain and Snutch (2012) and Tang and Thompson (2012) in the 4th edition of Jasper’s Basic Mechanisms of the Epilepsies. A number of abnormalities reported in epilepsy models may interact with the intrinsic dendritic properties described above to enhance dendritic burst generation. These conditions include loss or a decrease in GABAergic postsynaptic inhibition due to cortical trauma (Gu et al., 2017), genetic mutations that decrease the output of parvalbumin interneurons (Ogiwara et al., 2007), status epilepticus (Cossart et al., 2001; Perez-Ramirez et al., 2020), cortical malformations (Rosen et al., 1998), and other pathophysiological processes that would mimic the effects induced by penicillin (i.e., enhanced dendritic burst generation), thereby contributing to PDS generation and epileptogenesis.

Widespread axonal sprouting after injury increases excitatory synaptogenesis on dendrites and provides synchronization of epileptogenic burst generation in populations of neurons (Jin et al., 2006; Perez-Ramirez et al., 2020; Salin et al., 1995; Takahashi et al., 2018). Other pathophysiological abnormalities such as pharmacological reductions in K⁺ currents (Perreault & Avoli, 1991, 1992; Rutecki et al., 1987, 1990), and acquired or genetic reductions in K⁺ channels can contribute to enhancing bursting and associated PDSs (Huang et al., 2009; Tiwari et al., 2020; for review, see Cooper, 2012). Increased NMDA-mediated synaptic activity in dendrites, as occurs in the low Mg²⁺ model of epileptiform synchronization (Thomson & West, 1986, p. 198; Traub et al., 1994), can also contribute to PDS generation.

Concluding Remarks

Since the early identification of the PDS as the interictal cellular counterpart of the focal interictal epileptiform spike (Li, 1959), much work has been directed toward uncovering the underlying cellular mechanisms. Over the past 60 years, research into epileptogenesis has characterized a large number of specific pathophysiological changes in brain structure and function that can result in generation of the PDS and underlie different epileptic disorders. As would be expected for a condition with multiple etiologies, the admixture of contributions to PDS generation will vary and include enhanced synchronous excitatory and/or inhibitory synaptic inputs, disinhibition that leads to enhanced excitation and dendritic Ca²⁺ channel activation, intrinsic and acquired membrane ion channel and receptor abnormalities, and so on. The interictal “spike” and PDS remain as important bioelectric guidepost for identifying and localizing epileptogenic brain areas and for experiments focused on exploring underlying pathophysiology and potential approaches to preventing epileptogenesis and epileptic disorders.

Acknowledgments

Disclosure Statement

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