Abstract

According to a classical concept in epilepsy research, seizures are triggered by an “imbalance” between excitatory (glutamatergic) and inhibitory (GABAergic) synaptic transmission. Recent work has shown, however, that not only the efficacy but also the qualitative mode of action of GABAergic signaling is controlled by ionic plasticity, which is mediated by activity-dependent changes in the driving force of currents across GABA_A receptors (GABA_ARs). We will briefly describe the basics of neuronal Cl⁻ and pH/HCO₃⁻ regulation, and the main functions of neuronal carbonic anhydrases and the Cl⁻ transporters, KCC2 and NKCC1. A major topic of discussion is how depolarizing currents carried by bicarbonate and by sodium across GABA_ARs and ionotropic glutamate receptors, respectively, act in a synergistic manner, leading to massive neuronal uptake of Cl⁻ and large extracellular K⁺ transients. These transmembrane ion fluxes form a major constituent of a positive feedback cycle, in which neuronal excitability is boosted by, and contributes to, the ionic shifts. Initially, this leads to an erosion of the inhibitory restraint in the region surrounding the ictal core, followed by a subsequent transformation to functionally excitatory GABA action (which is independent on NKCC1). In line with this, a wealth of evidence shows that intense activation of cortical interneurons often has a seizure-promoting effect. The synaptic and non-synaptic mechanisms associated with GABAergic excitation shed light on the complex spatiotemporal profiles of seizure generation and propagation, and they provide a rational basis for the loss of efficacy of GABA-enhancing antiseizure drugs on ongoing seizure activity.

Introduction

A major lesson learned during more than 100 years of epilepsy research is that the human brain, whether healthy or diseased, is susceptible to seizures. Seizures can be provoked acutely during the course of life by birth asphyxia, infections, cerebrovascular events, and concussion (Beghi et al., 2010; Hauser and Beghi, 2008), while seizures which occur spontaneously indicate more chronic pathology (Beghi et al., 2010). In the latter case when the initial insult has developed into chronic epilepsy, the seizures (“ictal events”) become recurrent with a variable rate, from sporadic to multi-daily. Pathophysiological network activities known as interictal events (IIEs) are seen in the electroencephalogram (EEG) during the seizure-free intervals (Pillai and Sperling, 2006). Seizures are also associated with numerous neuropsychiatric and neurodegenerative disorders including autism, Rett syndrome, and Alzheimer’s disease (Adan et al., 2021; Friedman et al., 2012; Robinson, 2012). There is increasing evidence that, rather than representing “comorbidities” of such diseases, seizures are a key part of their etiologies and provide a valid pharmacological target for ameliorating symptoms and perhaps even slowing down the progress of dementia (Lam et al., 2020; Sanchez et al., 2012). Thus, research on seizures has a clinical impact that goes beyond epilepsy.

The main aim of this chapter is to describe fundamental ionic mechanisms which involve endogenous, activity-dependent changes in intraneuronal chloride concentration ([Cl⁻]_i) and extracellular (interstitial) potassium concentration ([K⁺]_o). Dynamics in the concentrations of these two ion species play an important role in the initiation and evolution of seizures. These ionic mechanisms differ from the more subtle, modulatory actions brought about by changes in, for example, neuronal pH (Raimondo et al., 2015; Rasmussen et al., 2020; Ruusuvuori and Kaila, 2014). Our present task is greatly facilitated by the extensive body of evidence that the electrophysiological characteristics of seizures, particularly focal ones, are strikingly similar (de Curtis and Gnatkovsky, 2009; Jirsa et al., 2014; Perucca et al., 2014). This similarity extends from human cases with different types of etiologies to diverse animal models in vivo and in vitro. Thus, network patterns during seizure activity comprise an “attractor state” (to borrow a term from state physics) to which the network converges from a variety of starting conditions (Lopes da Silva et al., 2003).

In line with the “attractor-state” notion, current evidence indicates that the fundamental cellular network, as well as ionic mechanisms underlying the triggering, local evolution and spread of seizures, are amenable to valid experiments on healthy animals and on brain tissue thereof. Most of the work reviewed by us is based on this kind of research. Although one might think that the detailed mechanisms causing seizures would be best studied in vivo experiments from an epileptic brain, it has turned out that—rather surprisingly—evoking ictal activity in brain tissue from patients or animal models with chronic epilepsy is difficult and requires extreme conditions (Heinemann and Staley, 2014).

The invariant properties in neuronal activity patterns during focal seizures are associated with characteristic features of ionic redistribution. These transmembrane ion shifts are not mere side effects of neuronal activity—they are tightly involved in the generation, maintenance, and spread of seizures. During the last two decades, it has turned out that intense activation of GABAergic interneurons (INs) plays a crucial role. The postsynaptic actions of GABA_A receptors (GABA_ARs) in pyramidal (or more generally principal) neurons (PNs) can change from inhibitory to excitatory under various conditions, which reflects the ionic plasticity of GABAergic signaling (Kaila et al., 2014b; Rivera et al., 2005). As we will discuss herein, a fast transformation from postsynaptic inhibition to functional excitation caused by activity-dependent Cl⁻ accumulation commences at the onset of ictal events. Thus, the terms GABAergic and inhibitory are not synonymous, although this kind of implicit assumption (or semantic stance) is evident in numerous publications. Some other terms with potentially equivocal meanings within this framework need to be defined as well (see Box 6–1).

Box 6–1

Definitions.

We describe here the mechanisms whereby neuronal activity and ionic shifts interact and engage in positive feedback cycles to induce “ionic avalanches” which sustain epileptiform network events and their spread:

1.

the increase in the [Cl⁻]_i of PNs which is an activity-dependent process, and is able to reverse the driving force of postsynaptic GABA_AR-mediated currents, thereby compromising the efficacy of inhibition or turning inhibition into excitation; and

2.

the increase in the interstitial [K⁺] which is tightly associated with the early phase of a seizure and accounts for a significant part of the overall excitatory drive, including nonsynaptic effects.

Seizures in about 30% of patients with chronic epilepsy are not controlled by currently available antiseizure drugs (ASDs) (Kalilani et al., 2018), which reflects the lack of knowledge on the mechanisms of seizure activity in cortical (neocortical and hippocampal) networks. Another grave problem is the lack of efficient treatments for status epilepticus (SE) and neonatal seizures (Claassen et al., 2002; Donovan et al., 2016; Mayer et al., 2002; Pressler and Lagae, 2019; Wilmshurst, 2020). We believe that research on the ionic plasticity of GABA_AR signaling, as described in this review will provide novel insights not only for understanding the basic mechanisms underlying epileptiform activities and currently available ASDs, but also for the design of novel drugs.

Network Patterns of Focal Seizures

Focal Seizure Patterns: From Epilepsy Patients to Animal Models In Vivo and In Vitro

In patients with mTLE, intracranial hippocampal EEG recordings carried out during pre-surgery monitoring have shown that the most common types of seizures fall into two categories (Spencer et al., 1992). One of them begins with a sentinel spike followed by a low-voltage fast-activity (LVF) in the beta-gamma frequency range. The other has a hypersynchronous (HYP) onset seen as a brief train of large-amplitude spikes, on a background of markedly suppressed overall activity (see Jasper et al., 1951). The onset and initial ipsilateral spread of HYP-onset seizures was found to involve mesial temporal structures, whereas LVF-onset seizures involved mesial and lateral temporal as well as orbitofrontal cortex (Memarian et al., 2015; Velascol et al., 2000).

Importantly, the above seizure patterns in the human temporal lobe are reproduced in several in vivo animal models where seizures are experimentally evoked in the healthy brain. For instance, in a seminal study on rats with chronic kainate-induced epilepsy, Bragin et al. (2005) demonstrated a local onset of HYP seizures in the DG ipsilateral to injection, while LVF seizures commenced with a decrease of EEG amplitude and a parallel increase in frequency. With HYP, a marked increase took place in the amplitude of beta-gamma range frequencies, ripple frequency, and fast ripple frequency, whereas during LVF seizure, there was an increase in the beta-gamma range only. (That beta-gamma range oscillations are considered “fast” in the classical HYP/LVF nomenclature is different from what are currently considered “fast oscillations” per se in epileptiform events.)

In in vitro models based on brain slices, seizure-like events (SLE) with HYP onset commence with preictal “spikes” in the local field potential (LFP) (Avoli et al., 2016; Huberfeld et al., 2011). The preictal spikes are largely glutamatergic, and they are followed by a period of low-amplitude activity in the beta-gamma range. LVF seizures induced by 4-AP or by a brief pre-exposure to bicuculline are preceded by an initial LFP spike which is mainly GABAergic, as seen in parallel recordings of inhibitory postsynaptic potentials (IPSPs) in PNs in experiments on the isolated guinea pig brain in vitro (Gnatkovsky et al., 2008; Uva et al., 2015, 2005) and in rat brain slices (Lopantsev and Avoli, 1998). Regardless of whether the initial spike in the above seizure models is mainly glutamatergic (HYP) or GABAergic (LVF), the beta-gamma activity is accompanied by the onset of a K⁺ transient and a slow negative DC shift in the LFP (Avoli et al., 1996a, 1996b; D’Antuono et al., 2004; Kohling et al., 2016). After several seconds of beta-gamma activity, the cortical network patterns transform into canonical epileptiform bursts or extracellular spikes, both in vivo and in vitro.

The three acute models taking the center stage in the present review are (i) the 4-AP models in vitro (Perreault and Avoli, 1992, 1991; Voskuyl and Albus, 1985) and (ii) in vivo (Lévesque et al., 2013; Salami et al., 2015), and (iii) the 0-Mg²⁺ in vitro model (Anderson et al., 1986; Mody et al., 1987; Tancredi et al., 1990). Assays of neuronal properties and synaptic functions have shown that in all three models, the experimental maneuvers have a very fast effect on their proximal molecular and cellular targets (4-AP is a K⁺ channel blocker; and 0-Mg²⁺ removes the magnesium block of NMDARs). However, these immediate effects clearly do not represent a full explanation of why the above manipulations lead to epileptiform discharges, because these network activities develop only with a far longer latency. It is highly likely that—among other factors—the progressive, activity-dependent neuronal Cl⁻ loading and the K⁺ transients, which act in parallel contribute significantly to the evolution of epileptiform activities in both models.

Models Based on 4-Aminopyridine

4-AP is a powerful convulsant drug, and its actions have been extensively documented both in vivo and in vitro (Lévesque et al., 2013; Perreault and Avoli, 1989; Salami et al., 2015).

Mode of Action of 4-AP

4-AP has been employed as a pharmacologic tool for analyzing repolarizing K⁺ currents and synaptic transmission (Mitterdorfer and Bean, 2002; Thesleff, 1980). In a variety of preparations, 4-AP at concentrations of 10–50 µM has been shown to block the early transient A- and D-type K⁺ currents, (Storm, 1988), which leads to a strong and persistent enhancement of neurotransmitter release from excitatory and inhibitory presynaptic terminals (Buckle and Haas, 1982; Perreault and Avoli, 1989). This effect is presumably related to enhancement of Ca²⁺ influx caused by a prolongation of the presynaptic action potential (Perreault and Avoli 1989, and references therein). The block of voltage-gated K⁺ channels by 4-AP also enhances the tendency of several types of neurons (including INs) to produce bursts of spikes (Gnatkovsky et al., 2008; Librizzi et al., 2017; Uva et al., 2015).

Network Mechanisms in 4-AP Models

Following application of 4-AP, seizure-like events (SLEs) with LVF, and in some experiments with HYP onset, are typically observed in in vitro recordings from limbic and extralimbic areas. When intracellularly recorded from PNs of the entorhinal cortex in a brain slice, the LVF onset coincided with a depolarization that is associated with few, if any, action potentials in PNs and becomes hyperpolarizing when the membrane potential is brought to values less negative than –60 mV with current injection (Lopantsev and Avoli, 1998). Thus, the LVF onset of 4-AP-induced ictal discharges is associated with a period of robust and synchronous firing of GABAergic INs. Importantly, the seizures in the 4-AP model were not attributable to reduced postsynaptic GABAergic signaling, but rather the opposite.

The conclusion that GABAergic transmission was not compromised by lack of transmitter release or inhibition of GABA_ARs during seizure activity in 4-AP was further supported by experiments, in which synchronous IN discharges were observed at ictal onset (Lévesque et al., 2016; Librizzi et al., 2017; Uva et al., 2015; Ziburkus et al., 2006), and the ictal discharges were abolished by GABA_AR antagonists (Avoli et al., 1996a; Lopantsev and Avoli, 1998). In both entorhinal cortex slices and in the isolated brain preparation, a field spike associated with intense IN activity was observed at the onset of 4-AP-induced seizures (Gnatkovsky et al., 2008; Lopantsev and Avoli, 1998; Uva et al., 2015). Taken together, these data led to the proposal that the intense IN activity jump-starts the seizures (with the associated extracellular K⁺ transients; Avoli et al., 2016; de Curtis and Avoli, 2016). This conclusion gains support from considerations of the underlying ionic mechanisms, and also from the observations that standard ASDs, which enhance GABAergic signaling, such as diazepam and pentobarbital, have been shown to promote epileptiform activity in experimental febrile seizures and experimental SE when applied at low concentrations (Burman et al., 2019; D’Antuono et al., 2004; Ruusuvuori et al., 2013). These mechanisms may have clinical implications as will be discussed.

Optogenetic approaches have confirmed the involvement of specific neuronal classes in different seizure onset patterns in the 4-AP model. Selective stimulation of PV+ or SOM+ INs was sufficient to initiate ictal LVF onset events similar to those occurring spontaneously (Shiri et al., 2015; Yekhlef et al., 2015). Notably, the LVF-onset ictal events, occurring spontaneously during 4-AP application, switched to HYP-onset events when PNs (expressing calcium/calmodulin-dependent protein kinase II) were optogenetically stimulated in the entorhinal cortex (Shiri et al., 2016). In neocortical slices exposed to 4-AP, optogenetic stimulation of neurons expressing vesicular GABA transporter with a brief (30 ms) pulse triggered an interictal-like or ictal-like event (Chang et al., 2018).

The 0-Mg²⁺ Model

Mode of Action of Mg²⁺ Withdrawal

Another widely used model of acute epileptic activation in brain slices is based on removing Mg²⁺ ions from the bathing media (Anderson et al., 1986; Mody et al., 1987; Tancredi et al., 1990). In the absence of extracellular Mg²⁺ ions, the voltage-dependent Mg²⁺ block of NMDA receptors is removed, and the channels are activated by the presence of glutamate with no requirement for depolarization. NMDARs are >100 times more sensitive to glutamate than AMPARs (Patneau and Mayer, 1990), and the removal of Mg²⁺ ions results in a substantial enhancement of glutamatergic synaptic effects. Moreover, the reduction in the extracellular concentration of divalent cations in the 0-Mg²⁺ model leads to diminished “charge screening” at the extracellular side of the plasma membrane and to a consequent shift to less positive potentials required in the activation of voltage-sensitive channels (Hille, 2001). Interestingly, seizures associated with intense activity of fast-spiking INs are also observed following local NMDA injection in slices from the entorhinal cortex (Cammarota et al., 2013; Sessolo et al., 2015).

Network Mechanisms in the 0-Mg²⁺ Model

There are some notable differences between the 4-AP and 0-Mg²⁺ models. In 0-Mg²⁺, the earliest pathological discharges occur in neocortex and entorhinal cortex, whereas the hippocampal areas only start to display pathological activation much later (Codadu et al., 2019b). In contrast, 4-AP shows the reverse order of activation, with early and substantial involvement of hippocampal areas. A second difference is the relative levels of glutamatergic and GABAergic involvement in the early discharges: in 4-AP, these are almost purely GABAergic, whereas in 0-Mg²⁺ they involve both glutamatergic and GABAergic synaptic barrage (Codadu et al., 2019a). These distinct properties point toward differences in (i) the regional distribution of the ion channels that are directly affected by the experimental manipulations (the NMDA-Rs and the voltage-dependent K⁺ channels), and in (ii) the patterns of feedforward and recurrent neuronal connections.

The 0-Mg²⁺ model has been particularly helpful in providing insight into the spread of seizure activity from the ictal focus. The early discharges generate very large surround-inhibitory effects. In recordings from individual PNs ahead of an ictal wave front, one detects a very large glutamatergic current, greatly exceeding (often by an order of magnitude) the normal threshold for action potentials, and yet the PNs are prevented from firing by the concurrent feedforward inhibition (Trevelyan et al., 2006). These territories show distinctive LFP signals, with very prominent low-frequency field oscillations, indicative of large synaptic currents, but minimal high-frequency oscillations because there is little local neuronal firing (Schevon et al., 2012). The territories showing this signature LFP pattern are referred to as the ictal penumbra, in contrast to the ictal core territories, where all the neurons are displaying hypersynchronous firing.

A further interesting property of the 0-Mg²⁺ model is that after prolonged magnesium withdrawal, the SLEs in brain slices are replaced by recurrent epileptiform discharges (late recurrent discharges [LRDs]; see Figure 6–3) which resemble clinical EEG in convulsive SE (Anderson et al., 1986; Burman et al., 2019; Dreier and Heinemann, 1991). This LRD phase is considered the best available in vitro model of SE (Zhang et al., 1995), during which IN activity is highly synchronized with the network events.

Figure 6–3.

Progressive seizure activity drives pronounced depolarizing shifts in E_GABA and intracellular Cl⁻ accumulation in CA1 pyramidal neurons. A. The 0-Mg²⁺ model was used for LFP recordings of seizure activity, which progressed from SLEs (orange bars) (more...)

Activity-Dependent Ionic Mechanisms Underlying Fast Transformation from Inhibitory to Excitatory GABA_AR Signaling

Ionic Basis of the Reversal Potential and Driving Force of GABA_AR-Mediated Currents

The efficacy of postsynaptic inhibition depends on the driving force (DF_GABA = V_m− E_GABA) of GABA_AR-mediated currents. As shown in Figure 6–1, E_GABA is not identical to the equilibrium potential of Cl⁻ (E_Cl) but shows a marked deviation of up to 20 mV toward more positive values. This is attributable to (1) the substantial bicarbonate (HCO₃⁻) permeability (estimates of P_HCO3/P_Cl ranging from 0.2 to 0.5 [Bormann et al., 1987; Fatima-Shad and Barry, 1993; Kaila et al., 1989; Kaila and Voipio, 1987]) of GABA_ARs and to (2) the much less negative equilibrium potential of HCO₃⁻ (E_HCO3 ≈ –15 mV; E_HCO3 >> E_Cl) (for review of the original literature, see Kaila, 1994). Thus, the current component carried by HCO₃⁻ across GABA_ARs in, for example, resting neocortical PNs at low levels of [Cl⁻]_i is larger than that carried by Cl⁻ (Kaila et al., 1993). With regard to the generation of epileptiform events, the HCO₃⁻ mediated depolarization has a major impact because it leads to a conductive net influx of Cl^–  across the GABA_ARs and thereby to an activity-dependent positive shift in E_GABA. Thus, we see here the first elements of the positive feedback cycle (cf. Figure 6–4) between ion shifts and V_m, which are able to generate and sustain epileptiform activity.

Figure 6–1.

Ionic mechanisms that set the value of E_GABA and the driving force of GABA_AR currents. A. The GABA_A receptor channel is permeable to both Cl⁻ and HCO₃⁻, with estimates for the relative ratio of P_HCO3/P_Cl ranging from 0.2 to 0.5 (see Kaila, (more...)

Figure 6–4.

Schematic model of focal ictogenesis and the associated ionic avalanche. A representative LFP trace is shown (uppermost, 1–1000 Hz bandpass) with the preictal spike, followed by a period of low-voltage fast activity generated by INs, that precedes (more...)

Ionic Avalanches in the Generation and Spread of Seizures

Chronic Epilepsy and Long-Term Ionic Plasticity

Seizures in chronic focal epilepsy show a very high variability in their rate of occurrence, as well as propagation patterns, suggesting that there are numerous underlying causes and modulators at the molecular, cellular, and network levels. This heterogeneity of seizure-triggering mechanisms is in line with the fact that in the chronically epileptic brain, profound changes in neuronal plasticity, wiring, and viability have occurred at various stages during and after epileptogenesis. According to the main theme of the present review, our aim here is to provide an idea of the possible roles of ionic plasticity and especially of the Cl⁻ transport proteins NKCC1 and KCC2 in epileptiform activities. Ionic plasticity of GABAergic transmission can take place in a fast manner (within seconds) by (i) activity-dependent ion shifts, as described in the previous sections; or more slowly (from hours to days, months and years) by (ii) post-translational mechanisms acting on Cl⁻ transporters and channels (e.g., (de)phosphorylation and membrane trafficking; Chamma et al., 2013; Heubl et al., 2017), and by (iii) changes in their gene expression and protein turn-over rates (Kaila et al., 2014b; Virtanen et al., 2021). In research on chronic epilepsy rather than on seizures per se, the latter kind of mechanisms is of key importance.

To start with, it is worth noting the following:

1.

While KCC2 is a central neuron-specific protein, NKCC1 is expressed in a ubiquitous manner in practically all cell types within and outside the brain (Delpire and Gagnon, 2018; Russell, 2000). This notion has major consequences: it means that whole-tissue analyses of NKCC1 mRNA or protein, published in numerous studies, do not yield a meaningful quantification of neuronal NKCC1 levels (Virtanen et al., 2020). Single-cell mRNA analyses of brain tissue have shown that NKCC1 expression levels are orders of magnitude higher for instance in oligodendrocytes than in neurons (Virtanen et al., 2020; Kurki et al., 2022). Moreover, it has turned out that neurons express exceptionally low amounts of NKCC1 with NKCC1b as their main splice isoform, while NKCC1a dominates in glial cells, and that the developmental upregulation of NKCC1 is attributable to the non-neuronal splice isoform NKCC1a (Kurki et al., 2022). Interestingly, NKCC1 located in astrocytes and oligodendrocytes has powerful effects on neuronal signaling (Henneberger et al., 2020; Yamazaki et al., 2021). Thus, the wide expression patterns of NKCC1 and the high expression level of NKCC1a vs. NKCC1b, must be taken into account when studying the actions of NKCC1 blockers, such as bumetanide, whether applied systemically or directly into the brain (see Löscher et al., 2013; Löscher and Kaila, 2022; Puskarjov et al., 2014a; Tóth et al., 2021). Finally, we would also like to emphasize that Cl⁻ levels in neurons and other brain cells in vivo are not set by a balance between NKCC1 and KCC2; rather, [Cl⁻]_i dynamics is determined by Cl⁻ transporters and by conductive fluxes, especially those that take place across GABA_ARs (Doyon et al., 2016; Kaila et al., 2014a).

2.

When considering the role of KCC2 in chronic epilepsy or any other CNS disease, it is important to note that KCC2 is a multifunctional protein with numerous pleiotropic effects (Virtanen et al., 2021). Thus, while epilepsy variants of KCC2 associate with severe seizures (Kahle et al., 2014; Puskarjov et al., 2014b; Saito et al., 2017; Saitsu et al., 2016; Stödberg et al., 2015), this fact does not inform us about the roles of nonmutated KCC2 in focal seizures in general. Also, pharmacological block of the ion-transport function of KCC2 is not likely to mimic the multiple effects of gradual and protracted KCC2 down-regulation caused by neuronal damage.

Pioneering work on the intrinsic activity in chronically epileptic brain has shown that the human hippocampus and adjacent cortices produce IIEs in brain tissue resected from epileptic patients (Kohling et al., 1999, 1998; Schwartzkroin and Haglund, 1986; Schwartzkroin and Knowles, 1984). In a widely cited study, Cohen et al. (2002) showed that such events were blocked by antagonists of iGluRs but also of GABA_ARs. Intracellular recordings showed that INs tended to fire at the very onset of the IIEs. Further, while IPSPs in most PNs were hyperpolarizing, around 20% of PNs had a depolarizing GABA_AR response and often discharged during the IIEs. Most of these neurons had a decreased expression of total KCC2, as shown by immunohistochemistry and in situ hybridization (Huberfeld et al., 2007). Moreover, the in vitro IIEs were abolished by bumetanide, which indicates that the depolarizing GABA_AR responses were attributable to an NKCC1-dependent high steady-state [Cl⁻]_i in a subpopulation of PNs (see also Wozny et al., 2005, 2003). There is no information on whether the NKCC1 transport activity is altered by, for instance, an increase in the transporter protein levels in the afflicted neurons, or by post-translational mechanisms (see point 1 above). Notably, the NKCC1-dependent depolarizing and functionally excitatory GABA transmission that is able to drive IIEs is mechanistically distinct from what is observed following activity-dependent Cl^–  accumulation (see Figures 6–1 and 6–4).

While blocking NKCC1 by bumetanide in chronic epileptic tissue in vitro blocks IIEs, it is unlikely that application of the drug systemically (per os, i.p., or i.v.) suppresses seizures by acting on central neurons in vivo. The problems caused by the poor pharmacokinetic properties of bumetanide as a CNS drug (and the lack of cellular target specificity) have been extensively discussed elsewhere (Puskarjov et al., 2014a; Löscher and Kaila 2022). It has, however, been shown that in tissue resected from patients with chronic epilepsy, such as caused by glioma, bumetanide does block experimentally induced seizures (e.g., low-Mg²⁺/high K⁺; Pallud et al., 2014), which also show a sensitivity to clinically approved ASDs (Augustin et al., 2018; Jandová et al., 2006).

Numerous studies have shown a striking decrease in KCC2 expression following the induction of seizures in vivo and in vitro (Kaila et al., 2014b). The down-regulation of KCC2 in epilepsy—which is permissive for the generation of IIEs—has a fast onset in susceptible brain areas and neurons. The first study on this topic (Rivera et al., 2002) showed that following in vivo kindling and SE in mice, KCC2 mRNA fell steeply in the dentate gyrus within 2–6 hours. There is an extensive literature on the roles of brain-derived neurotrophic factor (BDNF) and the calcium-dependent proteolytic enzyme calpain and its endogenous antagonist, calpastatin, in epilepsy (Binder et al., 2001; Das et al., 2012; Feng et al., 2011; Gorter et al., 2007) and in the regulation of KCC2 protein levels (Puskarjov et al., 2012; Rivera et al., 2002; Wan et al., 2018); these will not be dealt with in detail here (Kaila et al., 2014b). However, it is interesting to note that while seizure activity reduces KCC2 expression in a BDNF-dependent manner in adult neurons (Rivera et al., 2004), an opposite effect takes place at an immature stage. In postnatal-day 5–7 rats, kainate-induced seizures led to a fast increase in the surface expression of KCC2 in CA1 pyramidal neurons (Khirug et al., 2010). The consequent precocious E_GABA shift—or, more accurately, the precocious increase in KCC2-mediated Cl⁻ extrusion—to a level similar to adult neurons might act as an endogenous seizure-suppressing mechanism in the immature brain.

Local genetic down-regulation of KCC2 in the mouse hippocampus has been shown to result in a disease state reminiscent of mTLE, including hippocampal astrogliosis (Kelley et al., 2018). While results of this kind are interesting, they may not be solely related to the reduction of neuronal K⁺-Cl⁻ cotransport, given that loss of KCC2 leads to numerous effects that are likely to get established during the time interval from transfection to experiment. The same applies to genetic manipulations leading to KCC2 upregulation (Magloire et al., 2019a; see previous section). In this context, it would be important to make parallel experiments using transport-inactive constructs of KCC2, which have been of crucial value in work on the morphogenetic effects of KCC2 that are mediated by neuronal cytoskeletal-associated proteins (Awad et al., 2018; Fiumelli et al., 2013; Li et al., 2007; Llano et al., 2015). Notably, a loss of both ion-transport and structural actions of KCC2 was observed in the first characterization of a KCC2 disease mutation, which was linked to febrile seizures (Puskarjov et al., 2014b) (and to idiopathic generalized seizures in a study on KCC2’s transporter role only [Kahle et al., 2014]).

The interictal activity in chronically epileptic tissue, and its ion-regulatory underpinnings, are highly reminiscent of NKCC1-dependent network events in the immature rodent hippocampus (Blaesse et al., 2009; Cohen et al., 2003; Huberfeld et al., 2011; Sipilä et al., 2005). It is tempting to postulate that GABA_AR signaling in post-traumatic neurons resumes its immature, depolarizing/excitatory mode of action (Cohen et al., 2003; Payne et al., 2003). Is KCC2 down-regulation thus an adaptive or a maladaptive mechanism from the point of neuronal survival? The advantages of down-regulation of KCC2 include a reduction in energy consumption (Buzsáki et al., 2007) and dedifferentiation at the level of neuronal morphology and synaptic contacts, which is required for a reestablishment of connections (Cohen et al., 2003; Payne et al., 2003; see also Joy & Carmichael, 2021). On the other hand, down-regulation of KCC2 as a maladaptive process is in line with the fact that numerous conditions of neuronal trauma which lead to decreased KCC2 expression, including, for example, stroke and mechanical damage with axotomy (Coull et al., 2003; Goubert et al., 2019; Jaenisch et al., 2010; Katchman et al., 1994; Nabekura et al., 2002; Topolnik et al., 2003; Vale and Sanes, 2000; Wang et al., 2014), are known to be also associated with an increased tendency for seizure generation and epilepsy.

Finally, we would like to point out that the question on the adaptive or maladaptive nature of specific disease-associated alterations at the molecular level, such as changes in the expression and functions of Cl⁻ transporters and channels in epilepsy, do most likely not have a simple yes/no answer. A very frequent fallacy when searching for causal factors in the progress of a given disease is to assume that “what is different is pathophysiological.” As aptly pointed out by Dalby and Mody in their review on epileptogenesis (2001), an open airbag in a car accident may seem to the uninitiated to be the cause of the crash. In general, research on CNS disorders and on novel therapies should be based on a broader recognition of evolutionary and developmental factors. These evo-devo factors do not only shape the mature brain but also its complex ways to respond to conditions which lead to various paths in and out of a specific disease or disorder.

Conclusions

An implicit assumption in most electrophysiological studies (and in practically all textbooks of neurobiology) is that the equilibrium potentials of the ions (namely, Na⁺, K⁺, and Cl⁻), which are mainly responsible for the generation of action potentials and postsynaptic responses, remain constant and, therefore, the changes in the corresponding ionic driving forces are solely caused by changes in V_m. This view implies that all activity-dependent changes in the properties of neuronal signaling and network functions are mediated by changes in synaptic plasticity or in the intrinsic properties of neurons. Indeed, the early work with K⁺-selective electrodes failed to detect activity-dependent [K⁺]_o transients in the CNS during normal physiological activity. In some cases, [K⁺]_o shifts with a modest amplitude were observed, for instance, in the spinal cord following intense nociceptive stimulation (Svoboda et al., 1988). Thus, ion shifts taking place in vivo were (and still are) mainly considered as “modulators” of—rather than active elements in—neuronal network functions. Our interest, however, concerns far more extreme levels of activation, during epileptiform events and especially seizures. The evidence presented in this review demonstrates that these events are not only modulated by substantial shifts in [K⁺]_o and neuronal [Cl⁻]_i, but that these ionic shifts are major causal factors in their generation, maintenance, and propagation.

A well-known example of an ionic modulatory effect is a local or global change in brain pH (i.e., in [H⁺] and/or [HCO₃⁻]), whereby an intra- or extracellular alkalosis enhances excitability, while an acidosis has the opposite effect (Ruusuvuori and Kaila, 2014). When alkaline shifts in brain pH evoke epileptiform activities (ranging from neonatal seizures to SE), a negative feedback cycle is activated: intense neuronal activity, including epileptiform events, leads to a local acidosis that suppresses the activity itself (Ruusuvuori and Kaila, 2014). In sharp contrast to this, the activity-dependent [K⁺]_o transients have a key role in the “ionic avalanche”, which is partly mediated by their immediate depolarizing and excitatory effects. Thus, a sufficiently high local K⁺ transient acts as a critical self-perpetuating factor in powerful positive feedback loops, which are immediately involved in the triggering and spread of various kinds of seizures. In theory, a selective block of the [K⁺]_o transients associated with seizures (which is obviously not experimentally possible but can be modeled; Kager et al., 2000) would lead to a suppression of seizure activity.

A major advance in our current knowledge on the generation of seizures is the discovery that cortical INs do not always act in an inhibitory manner. Thus, the fact that GABAergic transmission can undergo a fast transformation from inhibitory to functionally excitatory—and even seizure-promoting—in the mature CNS is not as “paradoxical” as was thought before. Notably, GABAergic signaling is directly linked—via multiple mechanisms—to the regulation of the transmembrane gradients of both Cl⁻ and K⁺ ions, and it is therefore well-posited to act as a hub in the mechanisms and consequences of the seizure-promoting ionic avalanche.

The diagram in Figure 6–4 is highly simplified and intended only to provide an idea on what the temporal evolution of seizure and the ionic avalanche would look like at a given cortical location. The spatial spread of seizures is much harder to visualize, as it requires us to consider the spatial dynamics of the ictal core and penumbra. The spread of activity may involve both the fast inter-areal spread of seizures through conventional axonal communication, inducing secondary sites of ictogenesis, and the [K⁺]_o transients involved in the local spread of seizures, which do not conform to neuronal wiring patterns. This latter propagation mechanism is likely to be a dominant factor behind the slow nonsynaptic spread of seizures within and across distinct brain regions.

A major challenge for further work is to gain detailed information of the mechanisms and consequences of the multiple modes of GABAergic signaling described in this review. One such consequence is evident in the loss of therapeutic action of GABA-enhancing ASDs on SE (Burman et al., 2019; Gaínza-Lein et al., 2019, 2018; Naylor, 2014), which is mirrored in in vitro experiments following pronounced Cl⁻ loading (and likely emergence of significant [K⁺]_o transients) by recurrent seizure activity (Burman et al., 2019; Figure 3). A similar problem is most likely related to the pharmacotherapy of neonatal seizures (Davidson et al., 2019).

While the introduction of novel concepts, such as the ionic plasticity of GABAergic transmission (Kaila et al., 2014b; Rivera et al., 2005), has enhanced our understanding of the generation and spread of epileptiform events, we still do not know the proximal mechanisms triggering recurrent seizures, often in a highly unpredictable manner, in acquired chronic epilepsy. Much of the classical work in this field was done on “disinhibited” slice preparations, in which seizure activity was induced by sustained block of GABA_AR-mediated transmission. However, there is little evidence that the early etiology of chronic epilepsy would involve such a mechanism. More recent work in this field has focused, instead, upon changes in the expression patterns and functionality of chloride transporters NKCC1 and KCC2, and time will show whether and how this approach might lead to breakthroughs in understanding the causes of epilepsy.

Acknowledgments

Disclosure Statement

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