Abstract

In families with febrile seizures and temporal lobe epilepsy, mutations affecting different GABAergic mechanisms suggest that failure of chloride conductance to limit depolarization may be directly epileptogenic. This “GABAergic disinhibition” hypothesis has been discounted historically for two reasons. First, early attempts to produce hippocampal sclerosis and epilepsy simply by eliminating hippocampal GABA neurons consistently failed to do so. Second, the notion persists that because clinical epilepsy diagnosis is typically delayed for years or decades after brain injury, temporal lobe epileptogenesis should be presumed to involve a complex pathological transformation process that reaches completion during this “latent period.” Recent advances clarify both issues. Although spatially limited hippocampal GABA neuron ablation causes only submaximal granule cell hyperexcitability, more spatially extensive ablation maximizes granule cell hyperexcitability and triggers nonconvulsive granule cell status epilepticus, hippocampal sclerosis, and epilepsy. Recent studies also show that disinhibited granule cells begin to generate clinically subtle seizures immediately post-injury, and these seizures then gradually increase in duration to become clinically obvious. Therefore, rather than being a seizure-free “gestational” state of potentially interruptible epileptogenesis, the “latent period” is more likely an active epileptic state when barriers to seizure spread and clinical expression are gradually overcome by a kindling process. The likelihood that an epileptic brain state exists long before clinical diagnosis has significant implications for anti-epileptogenesis studies. The location, magnitude, and spatial extent of inherited, autoimmune, and injury-induced disinhibition may determine the latency to clinical diagnosis and establish the continuum between the benign, treatable, and refractory forms of temporal lobe epilepsy.

Introduction

Temporal lobe epilepsy (TLE) is a fascinating neurological disorder in which seizures arise spontaneously from within the temporal lobe (Baulac, 2015). TLE can develop with or without associated brain pathology, and with or without histories of birth injury, traumatic brain injury (TBI), or prolonged febrile seizures in childhood (Earle et al., 1953; Meyer et al., 1954; Ounsted, 1967; Falconer and Taylor, 1968; Sagar and Oxbury, 1987; Mathern et al., 1995). Suspected causes of TLE include genetic mutations, developmental parenchymal and vascular malformations, brain infection, autoimmune encephalopathies, TBI, prolonged febrile seizures, status epilepticus (SE), inflammation, tumors, and stroke (Margerison and Corsellis, 1966; Mathern et al., 1994, 1995; Dalmau et al., 2011; Lancaster et al., 2011; Patterson et al., 2014; Vezzani et al., 2016; Wong et al., 2018; O’Connor et al., 2019; Graus et al., 2020; Perucca et al., 2020; Perucca and Scheffer, 2021; Tan et al., 2021). Although the similarity of clinical signs may reflect a common output of a disturbed temporal lobe network (Klein et al., 2018), the genetic factors, developmental anomalies, and the many pathologies that injuries produce have made the elucidation of the underlying epileptogenic mechanism unusually challenging. This chapter focuses on elucidating the relationships among pre-existing abnormalities, seizure and injury-induced neuron loss, GABAergic disinhibition, and the emergence of spontaneous epileptic seizures (epileptogenesis).

Three Steps to Refractory Temporal Lobe Epilepsy When Prolonged Febrile Seizures Are an Antecedent Factor

In 1966, Ounsted and colleagues, inferring a link between family histories of febrile seizures and afebrile epilepsy, concluded that “a child is genetically predisposed to febrile convulsions. The convulsions when they occur, chance to be severe, and in the course of them Ammon’s Horn is damaged. Sclerosis follows and an epileptogenic lesion arises” (Ounsted et al., 1966). The British neurosurgeon Murray Falconer concurred (Falconer and Taylor, 1968), and their shared conception of an inherited cause of febrile seizures implied that three sequential steps cause surgically treatable refractory TLE with hippocampal sclerosis (TLE-HS+). First, the inherited trait allows fever to trigger febrile seizures (Step One). If sufficiently prolonged, the febrile seizures cause “ischaemic cell injury” that results in mesial temporal sclerosis (Step Two). This hippocampal pathology in some way causes Step Three, a clinical epileptic state. As a result, both Ounsted (1967) and Falconer (1971) recommended that febrile seizures be aggressively suppressed, which was easier to propose than implement (French and Kuzniecky, 2014). It was also a controversial recommendation because febrile seizures were widely viewed at the time as benign, and even prolonged febrile seizures were seen as unlikely to damage the developing brain (Nelson and Ellenberg, 1978; Maytal et al., 1989; Haas et al., 2001). Experiments designed to understand “ischemic cell injury” soon put the assumption that “all febrile seizures are harmless” to the test.

Excitotoxicity, Neuron Loss, Disinhibition, and Temporal Lobe Epileptogenesis

The Latent Period; When after Injury Do Self-Generated Epileptic Seizures Begin?

Is the Latent Period after Nonconvulsive Status Epilepticus a State of Clinically Subtle Seizures or of No Seizures at All?

Immediately after the 24-hour period of afferent stimulation that reliably injured hilar neurons, granule cells were disinhibited and hyperexcitable to afferent excitation, and began to self-generate population spikes without delay (Fig. 24–1). The early pathophysiology was reliably associated with an acute pattern of hippocampal injury limited to the entorhinal cortex and hippocampus (Fig. 24–2), and perhaps a compensatory increase in GAD and GABA synthesis in dentate granule cells (Sloviter et al., 1996b). Months later, histological analysis (Fig. 24–3) revealed the hilar neuron loss that defines endfolium sclerosis in patients (Margerison and Corsellis, 1966; Bruton, 1988; Blümcke et al., 1999, 2000; Blümcke et al., 2013). The pathology included mossy fiber synaptic reorganization (Tauck and Nadler, 1985) 2 months post-injury (Fig. 24–3H), but it is relevant to emphasize that self-generated granule cell epileptiform discharges and focal behavioral seizures preceded mossy fiber sprouting, which has been discussed in detail previously (Sloviter, 1992; Sloviter et al., 2003, 2006, 2012; Frotscher et al., 2006).

Figure 24–1.

Granule cell hyperexcitability 1 day after 24 hours of perforant path stimulation. A and B. Evoked granule cell population responses to afferent stimuli in the awake state 1 day post-injury. A. Evoked responses to single stimuli at different voltages, (more...)

Figure 24–2.

Fluorojade-B (FJB) staining 4 days after 24 hours of perforant path stimulation. Green FJB fluorescence images were converted to grayscale and inverted to highlight FJB-positive neurons and neuropil, which appear darkly stained. A. Coronal section showing (more...)

Figure 24–3.

Hippocampal pathology 72 days after 24 hours of perforant path stimulation. A, C, E, and G. Sections from a control rat injected with retrograde tracer FluoroGold (FG) and perfusion-fixed with sulfide and aldehydes for subsequent Timm staining. B, D (more...)

Second, during the latent period (meaning the interval between injury and the first clinically obvious behavioral motor seizures), spontaneous granule cell epileptiform discharges and associated subtle behaviors (behavioral arrest followed by “wet-dog” shakes) occurred reliably, and the initial behavioral seizure onsets were always preceded by granule cell population discharges (Bumanglag and Sloviter, 2018). Thus, the latent period in this model is not a “seizure-free” latent period, but an interval of subtle focal seizures that increase in discharge duration (“self-kindling”; Teskey, 2020; Wolff et al., 2020) until they produce the first clinically obvious behavioral seizure (Bumanglag and Sloviter, 2018). If “epileptogenesis” literally means the birth of epilepsy (Sloviter, 2017), epileptogenesis in this model is immediate, and the latent period is a focal epileptic state in which the first seizures are clinically subtle and easily missed (Fig. 24–4). This experimental observation is consistent with the clinical features of benign TLE, in which subtle focal seizures frequently go undiagnosed (Labate et al., 2011).

Figure 24–4.

Granule cell layer epileptiform discharges recorded after 24 hours of perforant path stimulation. A. Spontaneous, clinically subtle seizure recorded 6 days post-injury compared to a clinically obvious seizure that occurred 49 days post-injury (B). The (more...)

Third, we unexpectedly discovered that, in all cases of spontaneous behavioral seizures, granule cell epileptiform discharges reliably started 5–12 seconds before the onset of each behavioral seizure (sudden awakening if asleep or the start of immobilization if awake). We also unexpectedly observed that clonic behavior stopped abruptly within ~1–2 seconds after the sudden termination of each epileptiform discharge. This was surprising because we had assumed that even if granule cells initiated each seizure, “downstream” neurons would maintain the seizure, which would then stop later for unknown reasons. However, the separate blinded analyses of the physiological and video recordings suggested that granule cell discharges open downstream “spring-loaded” (inhibited) doors, which abruptly “slam shut” as soon as the granule cell discharges stop (Bumanglag and Sloviter, 2018). The finding that granule cell discharges and behaviors are tightly linked temporally in epileptic animals does not preclude involvement of other surviving neurons, including neurons of the subiculum, area CA2, the entorhinal cortex, or the amygdala (Cohen et al., 2002; Wittner et al., 2009) as “upstream” initiators of seizures. However, all behavioral seizures observed were preceded by granule cell epileptiform discharges (Bumanglag and Sloviter, 2018). If granule cell discharges played no causal role in the behavioral seizures, some seizures would have been expected to occur without being preceded by granule cell discharges occurring. No such events were ever observed.

Fourth, granule cell layer epileptiform events that did not initially spread to become clinically obvious seizures were barely detectable by a recording electrode placed within the neocortex only ~3 mm above the dentate gyrus. The failure to detect these focal granule cell layer discharges from a nearby site parallels an observation by Pacia and Ebersole (1997), who compared intracranial and surface EEG recordings of seizure events in patients and reported that “discharges confined to the hippocampus produced no scalp EEG rhythms.” Thus, surface and intracortical recording in rats would be predicted to miss the focal granule cell-onset seizures that we recorded directly from the granule cell layer, and this false-negative scenario could easily create the erroneous impression that there is a prolonged seizure-free period after injury (Bumanglag and Sloviter, 2018).

In summary, prolonged nonconvulsive SE that produces the defining features of human TLE-HS+ causes immediate and persistent granule cell disinhibition, hyperexcitability, and self-generated granule cell-onset focal seizures that are temporally coincident with the initial hippocampal injury, and not delayed (Bumanglag and Sloviter, 2008, 2018). The limited brain injury produced in this model, and the relatively subtle pathology present in most patients with TLE-HS+ indicate that if the features of this animal model reflect the human condition, dentate granule cell behavior may be the primary determinant of the pathology, seizure onset, seizure phenotype, seizure duration, and seizure offset in TLE, regardless of whether granule cells initiate each seizure (Bumanglag and Sloviter, 2018). The finding that granule cell disinhibition and seizure onsets were temporally coincident refocused our attention on granule cell disinhibition as an immediately causal and sufficient epileptogenic mechanism.

Is Dentate Gyrus Disinhibition a Directly Epileptogenic Mechanism?

Can GABA Neuron Ablation Cause Prolonged Seizures, Hippocampal Sclerosis, and Epilepsy?

Spatially Limited versus Spatially Extensive Dentate Granule Cell Disinhibition

In the perforant path model, only extensive hilar neuron loss caused translamellar granule cell disinhibition (Zappone and Sloviter, 2004), and this extensive hilar neuron loss was associated with the immediate onset of spontaneous granule cell seizure discharges (Bumanglag and Sloviter, 2008, 2018). Based on these findings, we revisited the possibility that disinhibition might be directly epileptogenic despite our earlier failure to show that focal GABA neuron loss could cause epilepsy (Martin and Sloviter, 2001). We hypothesized that whereas the elimination of a small population of dentate GABA neurons, or a loss of GABA neurons in the pyramidal cell layers, was insufficient to produce “spontaneous” SE, hippocampal injury, and epilepsy, perhaps temporal lobe epileptogenesis simply requires disinhibition in a larger expanse of the granule cell layer.

Testing the Hypothesis That Spatially Extensive Disinhibition Is Directly Epileptogenic

Multiple SSP-saporin injections into a ~3 mm-long region along the longitudinal axis of the dorsal dentate gyrus had no immediate behavioral effects (Chun et al., 2019). However, starting ~3 days post-injection, rats began to exhibit episodes of abnormal immobilization, subtle facial automatisms, “wet-dog” shakes, and repetitive but subtle back-and-forth head movements (as though the rats were watching a tennis match). These easily missed behaviors continued for ~3–4 days and then stopped spontaneously. Months later, electrode implantation and granule cell layer recording in awake animals quickly revealed self-generated granule cell seizure discharges temporally associated with these focal seizures (Fig. 24–5). Histological analysis unexpectedly revealed extreme hippocampal sclerosis, which was surprising because there had been no behavioral indication, such as convulsive SE, that such an extensive and highly selective hippocampal injury was occurring.

Figure 24–5.

Spontaneous granule cell–layer activity in the awake state 96 days after Stable Substance P–saporin conjugate (SSP-saporin) injection in a normal rat. A. Spontaneous epileptiform discharge temporally associated with a clinically obvious (more...)

Recent recordings made in awake rats starting immediately after SSP-saporin injection confirmed that granule cell paired-pulse disinhibition started ~2 days post-injection, followed by hyperexcitable responses to afferent stimuli (Fig. 24–6A) and onset of self-generated granule cell layer population spikes and epileptiform discharges (Fig. 24–7A). These initial self-generated epileptiform discharges were followed by continuous high-amplitude granule cell layer events and discharges (Fig. 24–7B) that became the continuous granule cell SE and nonconvulsive behavioral SE described above. This nonconvulsive behavioral SE continued from ~3–8 days post-injection and then stopped spontaneously. Thus, SSP-saporin injection in normal rats produced self-initiating and self-terminating nonconvulsive granule cell SE, classic hippocampal sclerosis (Fig. 24–5), and granule cell-onset epilepsy (Chun et al., 2019). These findings suggest that spatially extensive disinhibition in the dentate gyrus may be an initiating cause of epilepsy. Although the causes of disinhibition in different patient subgroups are unclear, one could speculate that disinhibition might arise from: 1) an inherited or developmental abnormality that produces a “reduced-inhibition zone” within the inhibitory “contour map,” 2) from a malformation impinging upon the dentate gyrus (Sloviter et al., 2004), or, 3) from a combination of inherited disinhibitory defects plus granule cell disinhibition made worse by seizure-induced hilar neuron loss after prolonged febrile seizures or a TBI (Vespa et al., 2010; Lewis et al., 2014). Although granule cells are not normally spontaneously active (Alme et al., 2010; Pilz et al., 2016), disinhibited granule cells in SSP-saporin-treated animals responded abnormally to single afferent stimuli with remarkably prolonged epileptiform population discharges (Fig. 24–6A). Thus, granule cell disinhibition alone, whether caused by a genetic abnormality, neuron loss, or a combination of both disinhibitory influences, could be a primary and immediately epileptogenic mechanism.

Figure 24–6.

Dentate granule cell excitability after unilateral intrahippocampal injection of Stable Substance P–saporin conjugate (SSP-saporin) in a normal rat. A. Granule cell population responses to single stimuli to the angular bundle of the perforant (more...)

Figure 24–7.

Bilateral dentate granule cell layer activity in the awake state after unilateral intrahippocampal injection of Stable Substance P–saporin conjugate (SSP-saporin) in a normal rat. A. Self-generated granule cell layer activity ~95 hours post SSP-saporin (more...)

The finding that SSP-saporin injection reliably produced “spontaneous” nonconvulsive SE, chronic epilepsy, and an extent of hippocampal sclerosis rarely if ever seen in other animal models, is remarkable. This result raises the possibility that a preexisting disinhibitory defect of sufficient magnitude might allow fever to initiate prolonged febrile seizures and hippocampal injury in children without also injuring extrahippocampal structures because the excitation is spatially sequestered by surrounding inhibited structures. The unusually subtle focal behaviors of nonconvulsive SE (Chang and Shinnar, 2011; Shorvon and Sen, 2020) may explain why TLE patients, including those with endfolium- or hippocampal sclerosis, often report no known history of febrile seizures (Labate et al., 2011).

A Unifying Theory of Inherited and Acquired TLE Epileptogenesis

Step One: Initiation of Epileptogenesis

When the Preexisting Inherited Defect Results in Febrile Seizures

Step One of epileptogenesis when antecedent febrile seizures have occurred is suggested to be an inherited genetic abnormality that allows fever to initiate febrile seizures (Scheffer and Berkovic, 1997). The available evidence suggests that fever and inflammation may reduce inhibition (Kang et al., 2006; Olsen, 2006; Suchomelova et al., 2015), which, in tandem with the permissive influence of the inherited inhibitory abnormality, raises the risk of febrile seizures (Scheffer and Berkovic, 1997; Fernández et al., 1998; Wallace et al., 1998, Kasperaviciute et al., 2013; Puskarjov at al., 2014, Chan et al., 2015; Zhang et al., 2017).

When an Acquired Brain Injury, Rather Than an Inherited Trait, Causes Epilepsy

When TBI is the presumed cause of epilepsy, focal nonconvulsive seizures that can follow brain injury (D’Ambrosio et al., 2009; Vespa et al., 2010; Hsieh et al., 2017), if sufficiently intense and prolonged, are suggested to cause hilar neuron loss and immediate granule cell disinhibition (Lowenstein et al., 1992; Swartz et al., 2006; Parga Becerra et al., 2021). It is increasingly apparent that many patients with “acquired” TLE may also have a preexisting genetic component of susceptibility (Perucca and Scheffer, 2021). Regardless, in both inherited and acquired forms of TLE with hippocampal sclerosis, Step One presumably involves a prolonged period of dentate granule cell discharge, as evidenced by the presence of TBI-associated endfolium sclerosis (Swartz et al., 2006). However, this first step could also be any event, such as stroke or global ischemia, capable of causing neuron loss with or without prolonged excitation.

Is the Inherited Abnormality a Disinhibitory Defect?

What is the likely common mechanism of the many different inherited mutations that cause febrile seizures in childhood or afebrile epilepsy later in life? The studies described above using SSP-saporin to selectively eliminate GABA neurons suggest that the common mechanism may simply be impairment of chloride’s ability to weaken depolarizations. If different genetic mutations share the common property of reducing inhibition, the disinhibition need not require degeneration of GABAergic synaptic terminals (Ribak et al., 1979; Roberts, 1984), but it could be due to any derangement of the electrochemical chloride gradient (Kaila, 1994; Watanabe et al., 2019; Auer et al., 2020) that reduces granule cell inhibition (Staley and Mody, 1992; Walker and Kullman, 2012). Disinhibitory mechanisms could include death of inhibitory neurons (Ribak et al., 1979; Ribak, 1985), hippocampal malrotation or malformations that impinge upon the dentate gyrus (Fernández et al., 1998; Sloviter and Pedley, 1998; Sloviter et al., 2004; Shinnar et al., 2012; Scanlon et al., 2013; Tsai et al., 2013; Chan et al., 2015; McClelland et al., 2016), or the de novo generation of autoimmune antibodies to GAD or to GABA receptors (Falip et al., 2018; O’Connor et al., 2019; Graus et al., 2020; Perucca et al., 2020). Disinhibitory genetic mutations may involve GABA depletion due to inherited pyridoxine deficiency (Coughlin et al., 2019), decreased GABA release (Ryu et al., 2021), abnormal GABA receptors (Coulter, 1999; Kapur, 1999; Baulac et al., 2001; Sperk et al., 2004; Zhang et al., 2007; Houser et al., 2012; Kang et al., 2015), altered vesicular GABA transport caused by a mutated vesicular inhibitory amino acid co-transporter (Heron et al., 2021), altered chloride and potassium transport by neurons and glia (Miles et al., 2012; Puskarjov at al., 2014), astrogliosis-induced disinhibition (Ortinski et al., 2010; Robel et al., 2015), or any other mechanism that decreases the ability of the chloride gradient to weaken depolarization. The hypothesized disinhibitory defect could also result from a developmental failure to establish a normal “inhibitory map” postnatally that leaves disinhibited “patches” of granule cells. Other inhibitory defects could include a loss of excitatory input to inhibitory neurons due to seizure-induced neuron loss, malformations, or mutations (Sloviter, 1987, 1991b, 1994; Bekenstein and Lothman, 1993; Doherty and Dingledine, 2001; Jones et al., 2011; Zhou and Roper, 2011; Folweiler et al., 2020), abnormalities of the extracellular matrix surrounding inhibitory neurons (Schwarzacher et al., 2006; Tewari et al., 2018), or impairments of normal connectivity between granule cells and inhibitory neurons (Hoshina et al., 2021).

The paradoxical hyperexcitability caused by loss-of-function sodium channel mutations is likely explained by their selective expression in inhibitory neurons (Wallace et al., 1998; Ogiwara et al., 2007; Catterall et al., 2010; Cheah et al., 2012; Dutton et al., 2013). Other mutations also cause hyperexcitability without involving inhibitory neuron death (Jiang et al., 2016; Ekins et al., 2020; Sharma et al., 2021). For example, selective elimination of the CaV 2.1 (P/Q-type) voltage-gated Ca²⁺ channels from cortical parvalbumin-expressing inhibitory neurons, but not from somatostatin-positive interneurons, is sufficient to cause seizures (Rossignol et al., 2013). In addition, GABA neurons may initiate excitation by inhibiting other GABA neurons or by synchronizing excitation (Avoli and de Curtis, 2011; Ellender et al., 2014; de Curtis and Avoli, 2016; Khazipov, 2016; Fasano et al., 2017; Elahian et al., 2018; Weiss et al., 2019; Sharma et al., 2021). Thus, predicting the net effect of inhibitory neuron dysfunction is not straightforward.

The genetic features of Dravet syndrome illustrate how different disinhibitory mechanisms might be similarly epileptogenic. Most Dravet patients have a loss-of-function mutation of the sodium channel subunit SCN1A expressed selectively in inhibitory neurons (Wallace et al., 1998; Scheffer et al., 2001; Catterall, 2010). However, a small number of Dravet patients were found to have GABA receptor mutations (Scheffer et al., 2009; Carvill et al., 2014) or mutations in genes encoding Syntaxin-binding protein 1, which causes dysfunction in parvalbumin- and somatostatin-positive inhibitory neurons (Chen et al., 2020). The effect is presumably the same, and disinhibition is the suggested common mechanism. There may be no need to hypothesize a more complex epileptogenic mechanism than simple disinhibitory impairment of chloride conductance because the full epileptogenic cascade of events is replicated in normal animals simply by selectively eliminating GABA neurons (Chun et al., 2019).

The likely epileptogenic roles of inherited inhibitory defects do not preclude involvement of genetic mutations that directly cause granule cell hyperactivity (Pun et al., 2012) that normal inhibition cannot contain. Perforant path stimulation is an excessive excitatory event that overcomes a normal inhibitory state to initiate nonconvulsive SE, and it nonetheless results in neuron loss and granule cell-onset epilepsy (Bumanglag and Sloviter, 2018). It is not suggested that a primary defect in GABAergic inhibition must be the mechanism underlying Step One in all cases, but the febrile seizures or post-TBI seizures that presumably cause hilar neuron loss (Step Two) might decrease inhibition over a large expanse of the granule cell layer, and this secondary neuron loss-associated disinhibition could be sufficient to produce epilepsy.

When the Preexisting Defect Doesn’t Cause Prolonged Febrile Seizures in Childhood

The narrative above addresses the relatively small subset of cases in which inherited defects not only allow a fever to initiate febrile seizures, but the febrile seizures are so prolonged or intense that hippocampal injury results. Far more common are inherited factors that predispose to febrile seizures, but the febrile seizures cause no significant injury. Only ~5% of febrile seizures become febrile SE, and not all cases of febrile SE cause hippocampal injury (Shinnar, 2003; Lewis et al., 2014). Therefore, in most patients, Step One is probably the only step that occurs because most febrile seizures are not prolonged. The same preexisting disinhibitory defect is then hypothesized to cause epilepsy later in life, perhaps predominantly the benign form that constitutes a majority of TLE cases (Labate et al., 2011), with the resulting TLE without HS presumably being less severe and less refractory than TLE with HS (Fig. 24–8).

Figure 24–8.

A proposed scenario explaining the process of temporal lobe epileptogenesis with and without hippocampal sclerosis.

Unaddressed and Unanswered Questions

This chapter has focused primarily on the role of disinhibition in creating the epileptic brain state. Discussion of all hypothetical epileptogenic- and post-epileptogenic influences, what they may do to facilitate or delay epileptogenesis, and how different animal models relate heuristically to the human neurological disorder is beyond the scope of this chapter. However, if the perspective presented here has any validity, it implies the need to determine which of the many molecular and structural changes that follow brain injuries contribute to the formation of the initial epileptic state, which ones influence the clinical evolution of the already established epileptic brain state, and which ones play no significant role. For example, mossy fiber sprouting was originally assumed to be an aberrant excitatory circuit because it was assumed that the weeks before mossy fiber sprouting were “seizure-free” weeks, and that granule cells were incapable of generating spontaneous epileptiform discharges until mossy fiber sprouting became operational (Tauck and Nadler, 1985). The phenomenon of mossy fiber sprouting was so conceptually compelling that no attempts were made in early studies to determine whether spontaneous seizures preceded mossy fiber sprouting or if granule cell excitability increased as mossy fiber sprouting progressed (Tauck and Nadler, 1985; Cronin et al., 1992). The subsequent findings that maximal granule cell hyperexcitability and clinical epilepsy preceded mossy fiber sprouting (Sloviter, 1992, 2008), and that mossy fiber sprouting may have a compensatory, net inhibitory influence (Sloviter et al., 2006), illustrate the need to avoid biased assumptions and to relate candidate mechanisms to the timing of epilepsy onset and the level of population hyperexcitability at multiple time points post-injury.

It is also important to consider whether candidate mechanisms identified in animal models have relevance to humans. For example, dentate granule cell neurogenesis has been suggested to play an epileptogenic role in TLE (Bielefeld et al., 2014; Cho et al., 2015) despite longstanding doubts about whether granule cell neurogenesis even occurs in humans (Rakic, 2002). Although adult granule cell neurogenesis clearly occurs in primitive, short-lifespan mammals, and is increased by granule cell seizure discharges in rats (Parent et al., 1997), recent studies have strengthened the case that adult neurogenesis does not occur in long-lived and highly evolved mammals, including humans (Oppenheim, 2019; Duque et al., 2021; Sorrells et al., 2021). However, it is theoretically possible that although the rate of granule cell neurogenesis in the normal adult human brain may be nonexistent or extremely low (Franjic et al., 2022), human brain injuries reactivate this perhaps dormant physiological process by which the normal granule cell layer is initially formed postnatally (Goodman et al., 1993). Consideration of any role for granule cell neurogenesis in human epileptogenesis clearly requires its occurrence in humans, which is in doubt.

Synopsis

In summary, the hypothesis presented here is that the primary mechanism underlying temporal lobe epileptogenesis is inadequate chloride conductance (Kaila, 1994; Miles et al., 2012; Walker and Kullmann, 2012) that extends across a longitudinal expanse of the dentate granule cell layer. This mechanism, which requires spatially extensive granule cell disinhibition, is suggested because selective ablation of hippocampal GABA neurons outside the dentate gyrus (Rossi et al., 2010; Antonucci et al., 2012; Drexel et al., 2017; Spampanato and Dudek, 2017), or small injections made within the dentate gyrus (Martin and Sloviter, 2001; Chun et al., 2019), consistently failed to cause nonconvulsive SE, hippocampal sclerosis, and epilepsy. We regard the discovery that the spatially extensive elimination of GABA neurons replicates the sequential defining features of TLE with hippocampal sclerosis (Chun et al., 2019) to be compelling evidence that disinhibition alone can explain epileptogenesis.

Finally, it is hypothesized that when a fever lowers the seizure discharge threshold (Kang et al., 2006; Olsen, 2006; Suchomelova et al., 2015) in a child with an already lowered seizure threshold due to an inherited disinhibitory trait (Scheffer and Berkovic, 1997; Catterall, 2010; Puskarjov et al., 2014), febrile seizures can result (Patterson et al., 2014). If the seizures that occur during febrile illness or after TBI (Vespa et al., 2010) involve granule cell discharge, and the excitation is sufficiently prolonged, hilar neuron loss (endfolium sclerosis) results. If sufficiently extensive, this hilar neuron loss decreases granule cell inhibition further, causing spontaneous granule cell discharges because dendritic, somal, and initial segment depolarizations are inadequately shunted by chloride conductance (Fig. 24–8). These self-generated discharges can remain spatially sequestered for decades, or indefinitely, by their inability to overcome inhibited surrounding nuclei, resulting only in auras, sensory hallucinations, perceptions, or emotional sensations (Crompton et al., 2010; Labate et al., 2011; Perucca et al., 2017). Or they can “self-kindle” (Teskey, 2020) and eventually invade motor pathways, thereby becoming more clinically obvious. Thus, “epileptogenesis” may be a relatively simple, short-latency entity (Sloviter, 2017) that involves a reduction of chloride-mediated inhibition in an excitatory cell population of a particular aggregate size. The complexity may be in what comes after epileptogenesis, when epigenetic, molecular, structural, and pathological network processes influence the evolution and clinical features of the epileptic state throughout life. Fruitful therapeutic strategies might include an “anti-kindling” strategy to impede early seizure spread, methods that lessen or reverse disinhibition pharmacologically (Cǎlin et al., 2018) or by cell transplantation (Zhu et al., 2018), selective activation of “dormant” inhibitory neurons, or perhaps elimination of seizures by selectively ablating or silencing hyperexcitable granule cells on the offending side.

Acknowledgments

Disclosure Statement

References

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