Abstract

Hippocampal sclerosis (HS) is the most consistently observed histopathological finding in human temporal lobe epilepsy (TLE). Despite its long history, HS remains intriguing and continues to stimulate many questions about the functional significance of the histopathological alterations. Cell loss and gliosis have been hallmarks of HS since its earliest descriptions, and a classification system for subtypes of HS, based on the regions of predominant cell loss, was recently developed. These subtypes of HS are being studied in relation to clinical conditions and treatment planning, but the different patterns of histological changes could also inform studies of the basic mechanisms of TLE. While cell loss has been the focus of pathological studies of HS for many years, it has become increasingly important to consider the remaining neurons, as these are likely to be the sites of seizure initiation and propagation and thus the targets of treatment. Importantly, the major regions with remaining neurons (dentate gyrus, CA2, and the subiculum) all have unique morphological and functional changes that could influence epileptiform activity. Thus, the broad group of neuropathological changes in HS lead to numerous questions regarding their significance and functional effects, progressing from questions about the effects of different patterns of cell loss, to the influence of alterations in remaining neurons, and finally to consideration of the circuitry that could be established within the altered hippocampal formation. In this review, emphasis will be placed on studies of human HS, with inclusion of some related findings in animal models of epilepsy.

Introduction

Hippocampal sclerosis (HS) is the most frequently observed histopathological finding in drug-resistant temporal lobe epilepsy (TLE) (Blümcke et al., 2013), and the sclerotic hippocampus is considered to be a major source of epileptic activity in these patients. Successful seizure outcomes following surgical resection of regions with histopathologically verified HS support this suggestion (e.g., Lamberink et al., 2020). Thus, identifying the myriad of changes that occur in HS and determining their functional significance continue to be important challenges for the epilepsy field.

The histological changes in HS were first described by Sommer (1880), who noted the shrinkage of the hippocampus and called attention to cell loss in the region we now identify as CA1, previously described as Sommer’s sector. The descriptions were expanded by others (e.g., Bratz, 1899), and the histopathological changes were generally referred to as “Ammon’s horn sclerosis.” Margerison and Corsellis (1966) subsequently noted several variations in the patterns of cell loss and introduced the term “hippocampal sclerosis” to include both classical Ammon’s horn sclerosis and end folium sclerosis.

Views of HS have continued to evolve, expanding beyond a primary focus on cell loss to consideration of the remaining neurons and the changes that occur in these neurons. Throughout this process, studies of human HS have continued to inform our understanding of epilepsy and provoke further questions. Each neuropathological change in HS leads to questions regarding its significance and functional effects, progressing from questions about the effects of different patterns of cell loss, to the influence of alterations in remaining neurons, and finally to consideration of the circuitry that could be established within the altered hippocampal formation.

What Are the Patterns of Cell Loss in Hippocampal Sclerosis?

The classical pattern of HS was clearly illustrated by Bratz in the late 1800s (Bratz, 1899), and it is characterized by severe cell loss in what is now referred to as CA1 and the hilus, variable cell loss in CA3, and relative preservation of dentate granule cells and pyramidal cells of CA2 and the subiculum. Although this pattern has been identified consistently as the predominant pattern in HS, numerous variations in this general pattern are observed and additional patterns of cell loss have been described (Margerison and Corsellis, 1966; Bruton, 1988; Wyler et al., 1992; de Lanerolle et al., 2003; Blümcke et al., 2007). In a recent effort to provide greater consistency in the descriptions of HS, the International League Against Epilepsy (ILAE) proposed three major types of HS that could be applied to patients with temporal lobe epilepsy (TLE) (Blümcke et al., 2013). These descriptions focus on the predominant regions of cell loss, with semiquantitative estimates of the extent of cell loss.

In the present review, descriptions of these types of HS are modified in order to call greater attention to two functionally distinct regions that are enclosed within the arc of the dentate gyrus granule cells: the polymorphic (hilar) region of the dentate gyrus and the most proximal region of the hippocampus, identified here as CA3 (Fig. 2–1A). Distinguishing these subregions is important as they are associated with different parts of the hippocampal formation and can have different extents of cell loss in HS. The polymorphic region (referred to as the hilus in rodents) is a band of dispersed neurons that extends approximately 600 µm deep to the granule cells. In humans, as in rodents and other species, this region contains two broad classes of neurons that regulate the activity of the dentate granule cells: mossy cells and interneurons. Glutamatergic mossy cells form an associational pathway within the dentate gyrus and can influence granule cell activity at multiple levels along the longitudinal axis, while several subtypes of GABAergic interneurons provide inhibitory control of the granule cells (Amaral, 1978; Freund and Buzsáki, 1996). Thus, the neurons within the polymorphic region are an integral part of the dentate gyrus and functionally distinct from the adjacent pyramidal cells of the hippocampus.

Figure 2–1.

Hippocampal formation of normal human autopsy (A) and temporal lobe epilepsy (B–D) specimens that have been stained with cresyl violet to demonstrate neuronal cell bodies and illustrate the patterns of cell loss in the ILAE classification system (more...)

In the ILAE classification, the polymorphic region appears to be limited to a narrow band deep to the granule cells and is not specifically considered in the descriptions, although the broad region between the blades of the dentate gyrus, identified as CA4, is likely to include many of the neurons of the polymorphic region. However, the term “CA4” remains quite confusing and has been used to describe either the pyramidal cells within the arc of the dentate gyrus only (Allen Institute for Brain Science, 2010), the polymorphic region only, or the majority of the region between the blades of the dentate gyrus (Duvernoy et al., 2013), as in the ILAE description.

To avoid confusion with different uses of the term “CA4,” the pyramidal cells within the arc of the dentate gyrus are identified as CA3 in the current descriptions (Fig. 2–1A–D), consistent with the terminology of Amaral and colleagues for the human and monkey hippocampus (Amaral and Insausti, 1990; Amaral and Lavenex, 2007). These CA3 pyramidal cells and those outside the blades of the dentate gyrus appear to have similar connections, neurochemical characteristics, and cytoarchitecture, and thus currently can be considered as a single functional group.

In the ILAE classification system, HS type 1 is described as severe neuronal loss in CA1 and the broad region within the arc of the dentate gyrus (identified as CA4 in the ILAE description), with variable cell loss in CA3. This corresponds to the classical pattern of HS (Fig. 2–1B), and it is observed in 60%–80% of all TLE patients with hippocampal sclerosis (Bruton, 1988; Blümcke et al., 2013). In the illustrated example, there is substantial cell loss in both the polymorphic region and CA3, as well as in CA1, with relative preservation of granule cells and neurons in CA2 (Fig. 2–1B). In HS type 2, cell loss is found predominantly in CA1 (Fig. 2–1C). This pattern is less common but is found in 5%–10% of all TLE surgical cases (Thom, 2014). In a representative example, there is severe cell loss in CA1, consistent with the basic description of this pattern, but there is also substantial cell loss in the polymorphic region, even though many adjacent CA3 neurons remain (Fig. 2–1C). This distinction could be missed when the region enclosed by the blades of the dentate gyrus is considered as a single region. In HS type 3, cell loss occurs predominantly in the broad region within the arc of the dentate gyrus, with relative preservation of the other hippocampal fields, including CA1 (Fig. 2–1D). In the illustrated surgical specimen, both the polymorphic region and the proximal CA3 region exhibit substantial cell loss. This pattern is observed least frequently, occurring in 4%–7.4% of TLE surgical cases (Blümcke et al., 2013), and it appears to correspond to “end folium sclerosis,” described originally by Margerison and Corsellis (1966). In their schematic drawings of end folium sclerosis, the entire region enclosed by the dentate gyrus is identified as the end folium. However, the cell loss can also be restricted primarily to the polymorphic region (Bruton, 1988). The importance of the polymorphic (hilar) region, as part of the end folium, has been emphasized previously (Sloviter, 1994). An additional pattern of HS includes severe neuronal loss in all regions, also referred to as complete hippocampal sclerosis (Bruton, 1988), and is considered a variant of HS Type 1 in the ILAE classification. Astrogliosis is present in all three patterns of HS. In addition, some cases exhibit only astrogliosis without evident hippocampal cell loss and thus are not considered in the classification of HS (Blümcke et al., 2013).

Despite the importance of the polymorphic region, distinguishing this region from the adjacent, loosely organized cells of the proximal CA3 region is difficult with routine Nissl staining (Fig. 2–2A). However, Timm’s staining and dynorphin immunolabeling clearly delineate the polymorphic region in the normal human hippocampus, primarily due to strong labeling of axon terminals around mossy cells that are abundant within this region (Fig. 2–2B). The distinction between the polymorphic region and the adjacent pyramidal cells becomes important when considering cell loss in these regions, as marked cell loss occurs in the polymorphic region in many patients with classical HS, even when there is preservation of many neurons in the adjacent CA3 region (Fig. 2–2C).

Figure 2–2.

Normal autopsy specimens (A and B) and a temporal lobe epilepsy specimen (C) demonstrate the approximate boundaries of the polymorphic region. A. In a normal cresyl violet–stained section, it is difficult to distinguish the polymorphic region (more...)

In the current examples of HS, loss of neurons in the polymorphic region is evident in all three types of HS (Fig. 2–1B–D). This is consistent with previous descriptions in which cell loss was observed in the end folium in the majority of cases, regardless of the other patterns of cell loss (Margerison and Corsellis, 1966; Sloviter, 1994; Swartz et al., 2006).

A major goal of establishing a unified classification system for HS was to study possible relationships between the neuropathological subtypes and surgical outcomes and aid in characterizing specific clinicopathological syndromes (Blümcke et al., 2013). The different patterns of cell loss are also relevant for studies of basic mechanisms of epilepsy, as the underlying substrates and patterns of seizure development and propagation could differ among the subtypes. The different patterns of cell loss that occur in humans can also be related to animal models that exhibit similar patterns of cell loss, such as those with the classical pattern of HS and those with more restricted cell loss.

What Neurons Remain and How Are They Altered?

Alterations in Dentate Granule Cells

Substantial numbers of dentate granule cells are preserved in all of the HS subtypes, except in cases with nearly complete cell loss in all regions. The remaining granule cells are critical as they serve as the entry point to the hippocampal circuit (Dengler and Coulter, 2016, for review). Normally, granule cell activity is tightly controlled, with only sparse firing of small groups of neurons, consistent with their role in cognitive functions such as pattern separation and novelty detection (Jung and McNaughton, 1993; Leutgeb et al., 2007; Kahn et al., 2019). However, in many epilepsy models, there is a breakdown in this gate, and granule cell activity can be substantially increased (Heinemann et al., 1992; Krook-Magnuson et al., 2015; Dengler et al., 2017).

Numerous changes can contribute to increased granule cell excitability. First, compromised inhibition can lead to increased excitability through multiple mechanisms, including loss of GABA neurons or decreased GABA synthesis (Dengler et al., 2017, for review). In human TLE, despite preservation of GABA neurons in many regions, there is a loss of several subtypes of GABA neurons within the polymorphic region, including those expressing somatostatin, neuropeptide Y (NPY), and calretinin (de Lanerolle et al., 1989; Mathern et al., 1995; Sperk et al., 2007; Toth and Magloczky, 2014). Similar patterns of cell loss are consistently found in the hilus in animal models of TLE (Sloviter, 1987; Obenaus et al., 1993; Buckmaster and Dudek, 1997; Sun et al., 2007). In addition to deficits in inhibition, dentate granule cells exhibit morphological changes that could influence their excitability and propensity for seizure activity, including sprouting of their mossy fibers and disorganization of remaining granule cells.

Mossy Fiber Sprouting

The mossy fibers of dentate granule cells normally innervate neurons of the polymorphic region and CA3 pyramidal cells, but they do not innervate other granule cells. However, as demonstrated initially in a rat model of epilepsy (Tauck and Nadler, 1985), mossy fibers can form axon collaterals that project into the inner molecular layer of the dentate gyrus, form synaptic contacts with other granule cells, and thus create an aberrant excitatory circuit. This same pattern of supragranular mossy fiber sprouting has been found in human TLE, as demonstrated by Timm’s staining and dynorphin immunolabeling of the mossy fibers (Sutula et al., 1989; Houser et al., 1990; Babb et al., 1991). This sprouting can be robust in patients with HS and often forms a distinct band in the inner molecular layer of the dentate gyrus (Fig. 2–3A), and in some patients, extends aberrantly into CA2 (Fig. 2–3A) (Houser et al., 1990; Wittner et al., 2009; Freiman et al., 2021). Some degree of mossy fiber sprouting has been found in virtually all surgical specimens with HS but not in those without obvious cell loss (Proper et al., 2001; Schmeiser et al., 2017a).

Figure 2–3.

Dynorphin labeling of mossy fibers and terminals in the hippocampus of a patient with temporal lobe epilepsy. A. A densely labeled band of aberrant mossy fibers (arrows) is present in the inner molecular layer and extends around the entire border of (more...)

The ultrastructural features of the reorganized mossy fibers and their axon terminals are particularly striking in human tissue. These terminals can be quite large and are filled with clear, round synaptic vesicles, presumably containing glutamate, as well as a smaller number of dense core vesicles that contain dynorphin (Zhang and Houser, 1999) (Fig. 2–3B). They often contain numerous mitochondrial profiles, consistent with highly active terminals, and form distinct asymmetric (excitatory) contacts on granule cell dendrites and spines (Fig. 2–3B–D). A single mossy fiber terminal often forms multiple synaptic contacts on the same postsynaptic structure, as well as on different spines or dendrites (Fig. 2–3C). An interesting feature of the reorganized mossy fiber terminals is the presence of perforated synapses on dendritic spines (Fig. 2–3D). At such synapses, the postsynaptic densities are in close proximity but separated by nonsynaptic membranes that are indented to various extents and thus form a partition between the synaptic contacts (Fig. 2–3D). Perforated synapses have been associated with synaptic plasticity (Jones and Harris, 1995), and increased ratios of perforated to nonperforated synapses have been found in the molecular layer of the dentate gyrus after kindling and induction of long-term potentiation (Geinisman et al., 1990; Buchs and Muller, 1996). These and other studies have suggested that perforated synapses are associated with highly efficacious synapses, and, in studies of normal animals, immunogold labeling for both AMPA and NMDA receptors in CA1 was higher at perforated synapses than at nonperforated synapses, consistent with enhanced synaptic transmission at these synapses (Ganeshina et al., 2004).

The factors responsible for stimulating mossy fiber sprouting remain unclear. One proposed stimulus is the loss of mossy cells and other neurons in the polymorphic region (Houser et al., 1990; Babb et al., 1991). The mossy cells normally receive strong input from granule cells and project to the inner molecular layer, where they primarily innervate the proximal dendrites of granule cells. Thus, the loss of mossy cells could not only deprive the mossy fibers of some of their normal targets but also reduce the innervation of granule cells in the inner molecular layer. Both changes could serve as stimuli for reorganization of the mossy fibers. An association between loss of neurons in the polymorphic region and mossy fiber sprouting has been found in additional studies of humans with HS (Mathern et al., 1995; Proper et al., 2000; Schmeiser et al., 2017b), and a correlation between the extent of mossy cell loss and mossy fiber sprouting has been demonstrated in an animal model of epilepsy (Jiao and Nadler, 2007). However, selective deletion of mossy cells in an otherwise normal transgenic mouse did not lead to mossy fiber sprouting, at least at 5–6 weeks after mossy cell depletion (Jinde et al., 2012). These findings suggest that additional factors are likely to be involved in the stimulation of mossy fiber sprouting, but they do not rule out a role for the loss of mossy cells or other neurons in the polymorphic region as part of this process. Questions have also been raised about the contribution of adult-born granule cells to mossy fiber sprouting, and there is now evidence that both neonatal and adult-born granule cells contribute to mossy fiber sprouting in the inner molecular layer in a rat model of TLE (Althaus et al., 2016).

Despite the robustness of mossy fiber sprouting and the frequency with which mossy fiber sprouting occurs in humans and animal models of epilepsy, the functional effects and role of the sprouting in epilepsy remain unclear. Reorganized mossy fibers that create recurrent excitatory connections among granule cells would appear to be an ideal substrate for hyperexcitability of the hippocampal network and could be epileptogenic (Tauck and Nadler, 1985; Wuarin and Dudek, 1996).

Although increased granule cell excitability has been demonstrated in association with mossy fiber sprouting, additional modifications have often been required to unmask the effects of the sprouted mossy fibers, including reducing inhibition or increasing extracellular concentrations of K⁺ (Cronin et al., 1992; Hardison et al., 2000; Sutula and Dudek, 2007). This has led to questions about the relative strength of the reorganized connections and their contribution to the epilepsy process. In addition, severely reducing mossy fiber sprouting by prolonged administration of rapamycin, an inhibitor of the mammalian target of the rapamycin (mTOR) signaling pathway, failed to alter the development of seizures in a rat model of epilepsy (Buckmaster and Lew, 2011; Heng et al., 2013), leading to further questions about the contribution of mossy fiber sprouting to epileptogenesis (Buckmaster, 2014).

Nevertheless, in a study of surgically resected tissue from patients with TLE, slices from patients with HS and mossy fiber sprouting had a lower threshold for high K⁺-induced seizure-like activity in the dentate gyrus than those without sclerosis and associated mossy fiber sprouting (Gabriel et al., 2004). The patterns of epileptiform activity also differed, and tonic-clonic transients were superimposed on long-lasting field potential shifts exclusively in the slices with mossy fiber sprouting. These findings suggested that the network reorganization within the dentate gyrus could play a crucial role in determining the threshold for seizure-like activity in human TLE (Gabriel et al., 2004).

Recent studies with new experimental approaches have added support for a role for mossy fiber sprouting in network hyperexcitability. In an in vitro study of pilocarpine-treated mice, selective activation of the sprouted mossy fibers in the inner molecular layer, by a single light pulse, triggered action potentials in the postsynaptic granule cells, even in the absence of other manipulations to increase excitability (Hendricks et al., 2019). This, in turn, led to bursts of recurrent excitation of other granule cells, creating a reverberating circuit. These effects appeared to be due to increased release probability at the reorganized synapses, possibly related to a reduction in the tonic inhibitory effects of adenosine in the dentate gyrus (Hendricks et al., 2019). The investigators suggested that the sprouted mossy fibers act as spark plugs to hyperactivate the local dentate gyrus network. Recent in vivo studies in animal models, while not focusing specifically on the sprouted mossy fibers, also suggest that aberrant granule cell networks play a major role in spontaneous seizures and interictal epileptiform discharges in awake, behaving mice and that adult-born granule cells contribute significantly to this process (Zhou et al., 2019; Sparks et al., 2020). Such findings in animal models reinforce the need for continued studies of the role of mossy fiber reorganization in human TLE, where mossy fiber sprouting remains one of the most striking morphological changes in humans with HS.

Granule Cell Disorganization

Dentate granule cells are among the populations of neurons that are comparatively well preserved in hippocampal sclerosis, and yet some granule cell pathology is found in nearly all surgically resected specimens with HS (Blümcke et al., 2009). The alterations range from cell loss, with thinning of the granule cell layer or patches of cell loss within the layer, in approximately 38% of these cases, to architectural changes that include granule cell dispersion, bilamination, ectopic neurons, or clusters of neurons in the molecular layer in approximately 50% of the cases (Blümcke et al., 2009).

Two patterns of granule cell disorganization are particularly striking when compared with the relatively narrow band of granule cells in the normal dentate gyrus (Fig. 2–4A–C). Generalized granule cell dispersion is the most common pattern and is found in approximately 40% of patients with hippocampal sclerosis (Fig. 2–4B) (Houser, 1990; Armstrong, 1993; Thom et al., 2002). This pattern is characterized by a wider than normal granule cell layer, increased space between many of the granule cells, and poorly defined laminar borders, with numerous granule cells extending into the molecular layer (Fig. 2–4B). Rather than the rounded shape of normal granule cells, the dispersed neurons are often elongated, with processes extending vertically from either pole (Fig. 2–4E). Thus, the dispersed granule cells have many of the characteristics of migrating neurons, and some are aligned in vertical rows that extend into the molecular layer (Fig. 2–4E) (Houser, 1990; Liu et al., 2020).

Figure 2–4.

Granule cell cytoarchitecture in the human dentate gyrus of normal autopsy (A) and temporal lobe epilepsy (B–E) specimens as demonstrated by NeuN immunolabeling. A. In the normal dentate gyrus, granule cells (G) form a narrow, compact layer with (more...)

In a second architectural alteration, granule cells form a bilaminar pattern in which two layers of granule cells are separated by a clear region that is relatively devoid of neuronal cell bodies (Fig. 2–4C,D) (Houser et al., 1992; Armstrong, 1993). This pattern is observed less frequently than generalized dispersion and is found in approximately 10% of patients with hippocampal sclerosis (Thom et al., 2002). The pattern is intriguing as the two layers can be quite distinct, often with a thinner basal layer and a wider, more dispersed outer layer, and mossy fiber sprouting can occur above each layer.

These altered patterns of granule cells can vary in their extent at different levels of the hippocampus, as well as within the same section (Blümcke et al., 2009). While the layers of disorganized granule cells can be interrupted periodically by short segments of severe cell loss (Fig. 2–4D), the regions of dispersion or bilamination often contain numerous granule cells, and thus the alterations are not due simply to a loss of neurons in these regions (Houser, 1990; Thom et al., 2002).

Although granule cell dispersion has generally been considered unique to epilepsy, bilateral granule cell dispersion was found during an autopsy study of three infants (Harding and Thom, 2001). One of the children had a severe seizure disorder and bilateral hippocampal sclerosis, but the others had no seizure history. However, all three had neuronal migration defects, heterotopias, or polymicrogyria. Such findings suggested that granule cell dispersion could be an independent developmental disorder in some cases (Harding and Thom, 2001). Granule cell disorganization has also been described in pediatric patients with sudden unexpected death, although other regions of dysplasia were also found, consistent with a more general maldevelopment of the hippocampal formation (Kinney et al., 2016).

Recently, a retrospective study of a large number of pediatric cases reported granule cell dispersion in a high percentage of cases without a clinical history of epilepsy (Roy et al., 2020). The investigators concluded that granule cell dispersion was likely a variation of normal hippocampal anatomy and had no clinical significance. However, the alterations described in this study may not be identical to those observed in TLE. Currently there is no standardized method for identifying granule cell dispersion (Thom et al., 2005), but, in previous studies in TLE, dispersion has been identified only after multiple measurements along a straight segment of the granule cell layer, generally through the body of the hippocampus (Houser, 1990; Haas et al., 2002; Thom et al., 2002; Blümcke et al., 2009). Measurements at angles and undulations in the granule cell layer were avoided as disruption of the normal width of the layer and some dispersed granule cells are frequently observed at such locations, even in normal specimens (Blümcke et al., 2009) . More detailed operational descriptions of the alterations in TLE are needed in order to distinguish the patterns and extent of granule cell disorganization in TLE from those in other pathological conditions and normal tissue.

The suggestion that granule cell dispersion could reflect altered neuronal migration was initially based solely on the appearance and patterns of the granule cells (Houser et al., 1992). Considerable evidence now supports this view, and the specific cellular and molecular changes that lead to the altered granule cell patterns are being identified.

In TLE patients and a mouse model of epilepsy, the development of granule cell dispersion correlates with loss of Reelin function (Haas and Frotscher, 2010). Reelin, an extracellular matrix protein, is synthesized and secreted by Cajal-Retzius cells in the outer molecular layer of the dentate gyrus (D’Arcangelo et al., 1997; Del Río et al., 1997), as well as hilar somatostatin neurons (Alcántara et al., 1998; Gong et al., 2007), and is important for the proper lamination of the cerebral cortex and hippocampus. Haas et al. (2002) found that Reelin mRNA expression in Cajal-Retzius neurons is reduced in some patients with TLE, and the extent of loss of Reelin mRNA-labeled neurons was correlated with the extent of granule cell dispersion into the molecular layer. Reelin neutralizing antibodies in the hippocampus of normal adult mice induced granule cell dispersion (Heinrich et al., 2006). These and other findings suggest that Reelin plays an important role in the formation and maintenance of a compact granule cell layer and that Reelin deficiencies are likely associated with increased neuronal mobility and abnormal migration of granule cells along radial glia in the molecular layer (Frotscher et al., 2003; Fahrner et al., 2007). However, it is still not known whether the reduction in Reelin function is primarily related to loss of Reelin-synthesizing cells, a decrease in Reelin expression within remaining cells, or altered Reelin processing (Kobow et al., 2009; Duveau et al., 2011; Tinnes et al., 2011).

A recent proteomic study also suggests that alterations in neuronal migration contribute to granule cell dispersion in patients with TLE (Liu et al., 2020). Protein expression was compared in basal and dispersed granule cells of patients with granule cell dispersion, and 46% of the proteins were differentially expressed in the two groups of granule cells. Interestingly, the up-regulated proteins in the dispersed granule cells were involved in developmental migratory processes, including cytoskeletal remodeling, axon guidance, and signaling by the Ras homolog (Rho) family of GTPases. Subsequent immunohistochemical studies demonstrated Rho A immunolabeling in the poles of the cell soma in the outer, more dispersed granule cells, but not in the basal granule cells. Overall, the studies suggested that abnormal cellular migratory activities were linked to granule cell dispersion (Liu et al., 2020). There was only limited evidence to support ongoing adult neurogenesis (Liu et al., 2020), consistent with previous studies describing a lack of association between adult neurogenesis and granule cell dispersion (Fahrner et al., 2007). However, involvement of adult neurogenesis at earlier time points in the disease process cannot be ruled out.

The conditions leading to the abnormal migration and granule cell disorganization remain unclear. While neurodevelopmental alterations and genetic factors could be responsible for disorganization of the granule cells in some cases (Harding and Thom, 2001), it appears more likely that granule cell dispersion occurs as part of the overall processes associated with the development of HS, with the initial precipitating events producing specific cellular and molecular changes that, in turn, lead to altered architectural patterns.

Support for the development of granule cell dispersion following an initial insult, rather than from a developmental abnormality, comes from studies of the effects of inducing seizures in normal immature monkeys (Jürgen Wenzel et al., 2000). Following the induced seizures, the monkeys developed the classic pattern of hippocampal sclerosis as well as granule cell dispersion. Whether it is critical for the precipitating factor to occur during early development in humans remains uncertain, although some studies have suggested an association between granule cell dispersion and an early precipitating condition, such as severe febrile seizures, before the age of four years (Houser, 1990; Lurton et al., 1998; Blümcke et al., 2009).

Hippocampal cell loss appears to be one condition that is associated with granule cell dispersion (Lurton et al., 1997; Thom et al., 2005), and several studies have suggested that cell loss in the polymorphic region of the dentate gyrus could be particularly important (Houser, 1990; Thom et al., 2010). This region normally contains numerous somatostatin neurons, and loss of these neurons could contribute to a decrease in Reelin within the dentate gyrus (Gong et al., 2007). However, prominent granule cell dispersion is not found in several animal models in which there is severe loss of hilar somatostatin neurons, including the mouse pilocarpine model. Furthermore, the abnormal widening of the granule cell layer that occurs in the intrahippocampal kainate model in mice could be related to the direct excitatory effects of kainate (Suzuki et al., 1995; Chai et al., 2014), rather than cell loss.

Although granule cell dispersion is not a consistent or essential feature of HS and TLE, the displaced granule cells could contribute to recurrent excitatory connections among the granule cells, as they are located within the rich plexus of reorganized mossy fibers in the inner molecular layer. In addition, the altered locations of the granule cells within the overall circuitry of the dentate gyrus could contribute to deficits in learning and memory.

What Is the Circuitry among Remaining Neurons?

Recognizing the patterns of cell loss and preservation in HS leads directly to questions about the connections among remaining neurons in the hippocampal formation. All major regions with substantial neuron preservation have alterations that could lead to epileptiform activity as discussed in the previous sections, but the circuitry that allows this activity to spread through the hippocampus is less clear.

The patterns of HS could determine which regions within the circuit have the greatest influence on the initiation and propagation of seizure activity. With severe loss of neurons in CA3 and CA1, as in classical HS, activity of the subiculum could become a prominent driver of epileptiform activity or play a critical role in seizure generalization. The importance of the subiculum is supported by findings of a recent in vivo study of electrically evoked activity in humans with TLE (Tóth et al., 2021). While pathological activity could be recorded in all sampled regions (dentate gyrus, CA2/3, and subiculum), the patterns of activity differed among the regions, and only the subiculum was autonomously active under the recording conditions. Interestingly, high-frequency oscillations in the subiculum increased in parallel with the severity of cell loss in CA1 (Tóth et al., 2021).

In other patterns of HS, the trisynaptic circuit is better preserved, but alterations occur within the remaining circuit. For example, in HS with predominant loss of neurons in the polymorphic region and proximal CA3, with greater preservation of CA1, the dentate granule cells could play a prominent role in initiation of epileptiform activity, and this could be propagated through the remaining trisynaptic circuit. Granule cell activity and synchronization could be enhanced not only by the morphological changes, such as mossy fiber sprouting, but also by the loss of multiple subtypes of GABA neurons within the polymorphic region.

Even when the trisynaptic circuit appears severely disrupted in the examined sections, the circuit could remain intact at other anterior-posterior levels of the hippocampus. Neuropathological changes, including cell loss, mossy fiber sprouting, and granule cell disorganization, can vary substantially along the longitudinal axis of the hippocampus (Masukawa et al., 1995; Thom et al., 2002; Bernasconi et al., 2003; Thom et al., 2012; Coras et al., 2014). While more extensive cell loss and other neuropathological changes have often been found in the anterior hippocampus (Babb et al., 1984; Bernasconi et al., 2003), cell loss can also occur in posterior regions and even in the tail (Thom et al., 2012). In some cases, there can be substantial cell loss and axonal sprouting at one level and an apparent absence of morphological changes at other levels (Fig. 2–5A,B) (Houser, 1999). While the patterns of seizure initiation and propagation could be quite different at anterior and posterior levels, activity at one level could influence that at other levels through longitudinal connections within the hippocampal formation (Babb et al., 1984; Amaral and Witter, 1989).

Figure 2–5.

Dynorphin-labeled specimens from anterior (A) and posterior (B) regions of the dentate gyrus from a patient with temporal lobe epilepsy. A. At anterior levels, dynorphin labeling of aberrant mossy fibers is present in the inner molecular layer (M), with (more...)

The longitudinal connections of the hippocampus could also be altered and influence the propagation of seizure activity. Relatively little is known about such connections in the human hippocampus, but studies in rodents and monkeys suggest possible sources of such connections, and these could have implications for TLE. Mossy cells in the polymorphic (hilar) region are a major source of longitudinal connections within the dentate gyrus (Amaral and Witter, 1989; Buckmaster et al., 1996), and tracing studies have shown that the association fibers in this region can extend through 80% of the dentate gyrus in macaque monkeys (Kondo et al., 2008). In humans with TLE, as in related animal models, the numbers of mossy cells are often reduced (Blümcke et al., 2000; Seress et al., 2009), but the functional effects of mossy cell loss continue to be debated. Mossy cells form both direct excitatory and disynaptic inhibitory connections with distant granule cells, and it is not clear whether excitatory or inhibitory effects predominate (Scharfman, 2016, for review). However, if mossy cells were to have predominantly inhibitory effects on granule cells at distant levels, the loss of mossy cells could lead to enhanced propagation along the longitudinal extent of the dentate gyrus in TLE, and such functional effects have been proposed (Zappone and Sloviter, 2004). Recent optogenetic studies in a mouse model of epilepsy have provided support for this view, as silencing remaining mossy cells in the ventral dentate gyrus increased the propagation of seizure activity from ventral to dorsal levels and facilitated seizure generalization (Bui et al., 2018).

CA3 pyramidal cells also project for considerable distances along the longitudinal axis of the hippocampus in rodents and monkeys (Amaral and Witter, 1989; Li et al., 1994; Kondo et al., 2009). Thus, when there is preservation of CA3 neurons, their axonal projections could contribute to the development and propagation of seizure activity along the longitudinal axis, through axonal connections with remaining CA3 and CA1 neurons (Kondo et al., 2009).

The possibility that neurons of CA2 could contribute to the longitudinal connections of the hippocampal formation is intriguing as many neurons in this region remain in TLE and could form connections along the anterior-posterior axis of the hippocampus, including connections with the subiculum.

Clinical studies also suggest that longitudinal connections within the hippocampus are important for the propagation and synchronization of ictal activity throughout the hippocampus (Umeoka et al., 2012). In a series of patients with nonlesional TLE with hippocampal onset, hippocampal spikes were consistently synchronized along the entire length of the hippocampus, and this synchronous activity was considered necessary for the spread of seizures beyond the hippocampal structures. Following hippocampal transections between the head and body of the hippocampus, the synchronous hippocampal spikes were abolished beyond the head (Umeoka et al., 2012). Although the axonal pathways that are interrupted with such transections remain unknown in humans, transverse transections of the dentate gyrus, with interruption of the association pathways within the hilus, blocked seizure spread into posterior regions of the dorsal hippocampus in a mouse model of epilepsy (Pallud et al., 2011). Clinical studies have also suggested the effectiveness of multiple surgical transections of the hippocampus in seizure reduction in patients who are not candidates for hippocampal resection (Koubeissi et al., 2016). Together, these studies suggest that longitudinal connections within the hippocampus could serve as seizure-promoting circuits, and their interruption could be critical for seizure control.

Finally, the circuitry that leads to seizure initiation and propagation could be modified by reorganization of synaptic connections beyond the sprouting of mossy fibers. Evidence for such reorganization in human HS is limited, primarily due to the lack of adequate tracing methods. However, numerous studies have demonstrated axonal reorganization of additional pathways in animal models of epilepsy, including sprouting of CA3 and CA1 pyramidal cells, both locally and along the longitudinal axis of the hippocampal formation (Esclapez et al., 1999; Cavazos et al., 2004).

In contrast to the current lack of evidence for reorganization of many pyramidal cells in human HS, evidence of sprouting of remaining GABA neurons is extensive (de Lanerolle et al., 1989; Mathern et al., 1995; Arellano et al., 2004; Magloczky and Freund, 2005; Wittner and Maglóczky, 2017). While such alterations in GABA neurons appear counterintuitive, considering the deficits in functional inhibition in many regions, the increase in GABAergic innervation, particularly at perisomatic locations, could contribute to the synchronous firing of principal cells (Cobb et al., 1995).

Future Directions

Despite its long history, HS continues to provide new insights into the disease process and remind us of the changes that actually occur in a high percentage of patients with temporal lobe epilepsy. Current studies of HS emphasize the need for stronger integration of the findings in human tissue and those in animal models. While different patterns of cell loss and their possible clinical significance are attracting increased attention in human tissue, these different patterns are often not recognized or considered in studies of animal models of epilepsy. Likewise, while the functions of the dentate gyrus and related hilar neuron loss have been the focus of numerous studies in animal models, the neurons within the equivalent polymorphic region of the dentate gyrus are often not considered as a distinct functional group in neuropathological studies of human tissue.

Rapid advances in structural and functional neuroimaging will allow many of the changes identified in histopathological studies of HS to be studied in vivo in humans. Ideally, with increasingly higher resolution imaging and the development of new methods of analyses, it will be possible to identify the different patterns of cell loss and their occurrence along the full extent of the hippocampal formation, including the contralateral, less affected, side (e.g., Coras et al., 2014; Steve et al., 2020). Such studies could potentially aid in surgical planning and be correlated with clinical studies of memory and cognitive function.

Identifying alterations along the longitudinal axis of the hippocampal formation, and the connections between these regions, is becoming increasingly important as such changes could have major influences on the sites of seizure initiation and, potentially, the development of epilepsy. Likewise, studies of structural and functional connectivity will greatly increase our understanding of the wider networks that are involved in seizure activity and its generalization, as well as the functions of the anterior and posterior hippocampus (Poppenk et al., 2013; Blessing et al., 2016; Dalton et al., 2019; Chang et al., 2021). Such advanced imaging studies in humans can be complemented by in vivo electrophysiological studies in animal models, using new methods for selectively activating or silencing specific regions and cell groups.

Histopathological studies of human tissue can only provide information about the chronic state, and thus imaging studies at multiple time points are needed for identifying the progression of the structural changes and disease processes, as well as the effects of treatment. Recent findings of cortical thinning over time in patients with TLE (Galovic et al., 2019), and the slowing of these changes following temporal lobe surgery (Galovic et al., 2020), emphasize the importance of such longitudinal studies.

Histopathological findings in HS also provide a framework for studies of the genetic, cellular, and molecular changes that are involved in ongoing seizure activity as well as changes that may have contributed to the development of epilepsy. For all of these studies, relating the findings to the histopathological changes associated with HS will aid in the interpretation of the results and could be particularly useful in advancing our understanding of previously identified changes.

Acknowledgments

Disclosure Statement

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