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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

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Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

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Neurogenesis and Epilepsy

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Persistent neural stem cells in the subgranular zone of the hippocampal dentate gyrus generate dentate granule cells (DGCs) throughout life. Many adult-born DGCs integrate into the pre-existing circuitry and acquire electrophysiological characteristics of mature DGCs. Mounting evidence implicates DGC neurogenesis in certain forms of hippocampus-dependent learning and memory and in the modulation of emotional behavior or anxiety. Data from rodent models of medial temporal lobe epilepsy (mTLE) show that prolonged seizures acutely increase adult DGC neurogenesis, but the functional implications of altered neurogenesis in mTLE are poorly understood. Accumulating evidence suggests, however, that altered neurogenesis contributes to several well-characterized cellular abnormalities seen in experimental, and probably human, mTLE. These abnormalities include mossy fiber sprouting, DGC layer dispersion, and the appearance of DGCs in ectopic locations or with abnormal hilar basal dendrites. In contrast, other work suggests that adult-born DGCs that integrate normally during epileptogenesis may serve a compensatory role to restore inhibition. Current work aims to define the mechanisms by which epileptogenic insults alter adult neurogenesis, and whether restoring normal neural stem cell behavior after such insults will attenuate the development of epilepsy or its co-morbidities.

Medial temporal lobe epilepsy (mTLE) is a common and often intractable form of epilepsy. Approximately 50 million people suffer from different epilepsies worldwide,1 30–40% of whom may continue to have poorly controlled seizures despite therapy.2, 3 mTLE is estimated to be the most common cause of intractable epilepsy in this population.4 In addition to chronic seizures, the long-term morbidity of mTLE includes an increased incidence of depression5, 6 and problems with learning and memory7, 8 that may progress despite adequate seizure control.9 Thus, progress in the study of mTLE is critical for developing better therapies to ease the large burden of this disorder.

Humans with mTLE often have an initial “precipitating” event, followed by a latent period and subsequent development of epilepsy later in life. This knowledge has led to the development of the most common animal models of mTLE. In these models, a prolonged seizure (termed status epilepticus or SE) is induced by either electrical stimulation or a chemoconvulsant, leading to injury as the “initial precipitating event.” After a seizure-free latent period, spontaneous seizures develop and persist for the lifetime of the animal.10, 11 The two most commonly used chemconvulsant-induced SE models of mTLE are the kainic acid and pilocarpine models.

ADULT NEUROGENESIS IN THE EPILEPTIC BRAIN

Neurogenesis persists throughout adulthood in mammals, specifically in the subgranular zone of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the forebrain lateral ventricles. Neural progenitor cells migrate from the dentate subgranular zone to the granule cell layer, and from the SVZ through the rostral migratory stream into the olfactory bulb. While the majority of cells are generated early in life, new dentate granule cells (DGCs) arise at a lower rate throughout adulthood and into senescence both in rat12, 13 and human.14, 15 Adult-born neurons make up about 6% of the granule cell layer in rats16 and these cells are thought to integrate into hippocampal circuitry and acquire characteristics of mature DGCs.17, 18 Additionally, BrdU labeling studies indicate that DGCs born during adulthood that become integrated into circuits will survive to maturity. These DGCs are very stable and may replace DGCs born during development.19 Adult-born neurons are thought to play an important role in certain types of learning and memory or in regulating anxiety.20–25

In the rat pilocarpine model of mTLE, the rostral SVZ exhibits increased neurogenesis within weeks following prolonged seizure activity.26 Neuroblasts generated in the SVZ migrate more rapidly to the olfactory bulb, and some exit the migratory stream prematurely.26 As assessed by the expression of Ki-67, an endogenous cell proliferation marker, or short-pulse bromodeoxyuridine (BrdU) mitotic labeling, the dentate gyrus also responds to SE by increasing cell proliferation in the subgranular zone.27, 28 After either pilocarpine- or kainic acid-induced SE, dentate gyrus cell proliferation increases 5–10 fold after a latent period of several days and persists for several weeks.27, 29 In the dentate, this early proliferative response seems to be mediated by radial glial-like neural progenitor cells,30 as well as through activation of transit amplifying cells that are actively proliferating before SE.31 Interestingly, even single seizure-like discharges modestly increase DGC neurogenesis.32 Between 75–90% of cells newly generated after SE express mature DGC markers within 4 weeks,27, 28 and SE appears to accelerate the maturation and integration of adult-born DGCs.33

Approximately 3–4 weeks after a SE episode, proliferation rates return to baseline levels.27 In fact, chronic mTLE is associated with a decrease in neurogenesis as levels are substantially below baseline by 5 months after kainic acid-induced SE.34 These findings may also be relevant to human epilepsy, as the dentate gyrus of children who have had frequent seizures shows decreased numbers of proliferating cells and immature neurons.35 Potential reasons for this decrease include exhaustion of the progenitor pool, loss of needed growth/trophic factors or altered cellular interactions (reviewed in 36).

MORPHOLOGICAL ABNORMALITIES IN mTLE: ROLE OF NEUROGENESIS

The epileptic hippocampus in human mTLE is associated with numerous cellular abnormalities including CA1 and CA3 pyramidal cell loss as well as hippocampal astrogliosis. Damage to the hilus of the DG, known as endfolium sclerosis, is the most commonly observed lesion in the brains of patients with mTLE.37 SE provoked by kainic acid or pilocarpine mimics this phenotype, destroying about half the neurons in the dentate hilus.38, 39 The human DG also shows distinct morphological abnormalities including mossy fiber sprouting, granule cell layer dispersion, ectopically-located DGCs, and DGCs with very prominent hilar basal dendrites (HBDs).40, 41 In rodent models of SE such as the pilocarpine model, hippocampal pathways exhibit structural plasticity mirroring these changes.11

Mossy Fiber Sprouting

Mossy fibers are the axons of the hippocampal DGCs. The mossy fiber pathway normally projects to the pyramidal cells and interneurons of hippocampal area CA3 as well as to the dentate hilus. In the non-epileptic brain, this pathway is thought to make few, if any, recurrent synapses onto granule cells. A common feature of human mTLE,40,41 however, and of animal models of temporal lobe epilepsy, is the development of numerous mossy fiber-granule cell synapses.42, 43

In the epileptic human dentate gyrus, Timm staining, dynorphin immunoreactivity, and biocytin fills reveal that mossy fibers sprout into the dentate inner molecular layer.41,44,45 In the rat pilocarpine model of mTLE, Timm staining, used to visualize the zinc present in mossy fiber axons, also reveals significant amounts of mossy fiber sprouting (MFS) in the dentate inner molecular layer.11 Electron microscopy studies demonstrate that mossy fibers synapse onto neighboring DGCs, creating recurrent excitatory synapses.42

Over a dozen years ago, we first hypothesized that mossy fiber sprouting in experimental mTLE arises from adult-born, rather than pre-existing, DGCs.27 When we used irradiation to kill adult-born cells in the setting of SE, however, we did not block inner molecular layer mossy fiber sprouting 4 weeks later, suggesting that DGCs generated after SE do not send axons aberrantly into the dentate inner molecular layer.31 To address this question more definitively, we recently used retroviral reporter labeling to birthdate DGCs in combination with low-dose irradiation to transiently suppress DGC neurogenesis.46 At 4 weeks after pilocarpine-induced SE in adult animals, we found that neither neonatally generated DGCs nor those born after SE contributed to sprouting, but instead only DGCs that were 2–4 weeks old at the time of SE showed aberrant axonal reorganization. This finding is consistent with retroviral reporter labeling studies from another group who observed that adult-generated DGCs born 4 weeks before kainic acid-induced SE contributed to inner molecular layer mossy fiber sprouting.47 When we labeled adult-born DGCs 4 days after SE but allowed the animals to survive 10 (instead of 4) weeks, in contrast, we found that the adult-born DGCs contributed robustly to mossy fiber sprouting (Figure 1).46

Figure 1. Mossy fiber sprouting by adult-born DGCs.

Figure 1

Mossy fiber sprouting by adult-born DGCs. A–C, Confocal images of coronal brain sections through the dentate gyrus of adult rats injected with RV-GFP and immunostained for GFP. A control received an injection of RV-GVP 4 days after saline treatment (more...)

The finding of mossy fiber remodeling only by developing or newborn, and not mature, DGCs has key mechanistic implications for understanding seizure-induced DGC plasticity. Rather than recapitulating development, mossy fiber sprouting after SE appears to involve an alteration of ongoing development. This sprouting is thought to be progressive in nature, beginning 2 weeks after SE and peaking around 100 days post-SE.11, 48 The idea that successive generations of adult-born DGCs sprout aberrantly as they develop is consistent with this progression of mossy fiber reorganization for several months after SE.11 In fact, the timing of transiently increased neurogenesis for 2–3 weeks after the initial seizures27 followed by a potential suppression of neurogenesis chronically,34 along with the delay in adult-born neurons manifesting aberrant axonal outgrowth, fits well with a model in which most or all of the newborn DGCs eventually sprout. Such a time course would lead to a peak in MFS at about 2–3 months after SE.

Hilar Ectopic Granule Cells

The vast majority of neurons born in the subgranular zone during adult life migrate into the granule cell layer. After SE, many DGCs migrate instead into the dentate hilus or through the granular layer into the molecular layer.27, 34, 49–51 These ectopic cells are found in rodent models of epilepsy (Figure 2),27, 49, 50 and similar ectopically located granule-like neurons appear in the epileptic human hippocampus.51, 52

Figure 2. Hilar ectopic DGCs in experimental mTLE.

Figure 2

Hilar ectopic DGCs in experimental mTLE. Prox1 immunolabeling of DGCs from adult rats 35 days after saline (Control, left panel) or pilocarpine treatment (Seizure, right panel). Note the abundant Prox1-immunoreactive DGCs in the hilus of the epileptic (more...)

Hilar ectopic granule cells may result from abnormal migratory behavior of DGC progenitors after epileptogenic insults, as SE appears to cause aberrant chain migration of DGC progenitors to the hilus and molecular layer.51 Some propose a critical period after the birth of adult-generated neurons during which they are vulnerable to being recruited into epileptogenic neuronal circuits,53 and indeed, we find that only DGCs generated after SE migrate ectopically.46 One proposed cause of the aberrant migration is loss of the migration guidance cue Reelin, which is expressed in the adult rodent hippocampus.54

Hilar Basal Dendrites

The persistence of hilar basal dendrites (HBDs), normally a feature of only immature DGCs, may be a mechanism contributing to hyperexcitability of adult-born DGCs in epilepsy. The percentage of granule cells with hilar basal dendrites is probably substantially higher in persons with mTLE,55 and this finding is recapitulated in several animal models in which prolonged seizures induce an increased percentage of granule cells with basal dendrites located at the hilar border and extending into the granule cell layer.56, 57 Many of these basal dendrites have numerous spines, suggesting they are post-synaptic to axon terminals.49, 50, 58 Using Thy1-GFP mice, Walter and colleagues53 found that almost 50% of immature granule cells in mice exposed to pilocarpine-induced SE exhibited HBDs, and newborn cells were even more severely impacted than immature cells. In the rat pilocarpine model, about a third of adult-born DGCs that are 2 weeks old at the time of SE, or born 4 days after SE, develop HBDs.46

Electron microscopy demonstrates that HBDs form asymmetric synapses and are innervated by mossy fibers, potentially creating recurrent excitatory circuits.59, 60 HBDs can form on granule cells as early as one week following SE. Although the molecular mechanisms for the persistence of these HBDs are not well-defined, they may involve changes in the glial scaffold.61

FUNCTIONAL IMPLICATIONS OF DGC ABNORMALITIES IN mTLE

A large body of information supports the hypothesis that cellular abnormalities such as mossy fiber sprouting, ectopic DGCs and HBDs contribute to epileptogenesis in experimental and human mTLE. The functional implications of these abnormalities, however, and the contribution of adult-born DGCs to intact or epileptic hippocampal network function remain unclear. Here we describe the potential effects on hippocampal function of the different types of seizure-induced plasticity associated with aberrant neurogenesis.

Mossy Fiber Sprouting

Seizures in mTLE have been proposed to result from hyperexcitability due to aberrant excitatory recurrent axon collaterals between granule cells.62, 63 Integration of light microscopic and EM data suggests that the majority of synapses formed by mossy fibers in the granule cell and molecular layers are with other granule cells, leading to recurrent excitation.42, 62, 63 Additionally, evidence suggests that normal GABA inhibition is diminished by mossy fiber terminals, further contributing to hyperexcitability.64 Recent data also suggest interventions to block mossy fiber sprouting reduce the severity of seizures.65

However, further levels of complexity likely underlie epileptic pathogenesis. Although the aberrantly sprouted mossy fibers clearly form at least some recurrent excitatory synapses with other granule cells, some work suggests that DGC sprouting contributes to the synaptic drive onto inhibitory interneurons.66 Anatomical analysis of epileptic rat hippocampi reveals that some aberrant granule cell axons densely innervate inhibitory neurons.42, 67 Furthermore, the density of mossy fiber sprouting may not be associated with the total number of lifetime seizures or the seizure frequency in experimental or human TLE.68 These data suggest that other mechanisms in addition to mossy fiber sprouting might contribute to enhanced hippocampal excitability during epileptogenesis.

Hilar Basal Dendrites and Hilar Ectopic Granule Cells

Many studies have found that compared with controls, an increased number of granule cells in epileptic rats extended a basal dendrite into the hilus, providing a potential route for recurrent excitation.59, 60 Modeling studies suggest that even a relatively small percentage of DGCs if hyperinnervated by excitatory input (so-called “hub” cells) could lead to spontaneous seizures.69 Adult-born DGCs with long HBDs that receive excessive excitatory input may be just such cells.

Hilar ectopic granule cells themselves are also thought to be hyperexcitable. They have been shown to be postsynaptic to mossy fibers and have less inhibitory input on their somata and proximal dendrites than DGCs in the granule cell layer.49, 70 This finding is consistent with results showing that hilar ectopic granule cells are more excitable than granule cells in the GCL, and they burst fire in synchrony with spontaneous, rhythmic bursts of area CA3 pyramidal cells that survive SE.50 Consistent with these data is the finding that ablating neurogenesis after SE, the time when ectopic cells form,46 attenuates subsequent epileptogenesis, with a reduction of the frequency and severity of spontaneous recurrent seizures.71

One study, however, suggests the opposite, namely, that adult-born neurons that integrate normally may compensate for hyperexcitability after an epileptogenic insult. Jakubs and colleagues72 induced SE with electrical stimulation and then labeled adult-born neurons with retrovirus expressing green fluorescent protein (GFP). They recorded from the GFP-labeled cells in acute hippocampal slices and found that they showed increased inhibitory drive and decreased excitatory input compared to GFP-labeled cells in controls and mature DGCs in epileptic rats. However, they only studied adult-born neurons that integrated normally. These findings suggest that increased DGC neurogenesis after SE leads to heterogeneous populations of adult-born DGCs, some of which integrate aberrantly and may become hyperexcitable, while others integrate normally and may restore inhibition (Figure 3).

Figure 3. Aberrant neurogenesis in experimental mTLE.

Figure 3

Aberrant neurogenesis in experimental mTLE. Schematic of the intact adult dentate gyrus (A) with a DGC progenitor in the subgranular zone (SGZ) giving rise to immature DGCs (arrows). In the epileptic dentate gyrus (B), mossy fiber sprouting does not come (more...)

CO-MORBIDITIES ASSOCIATED WITH mTLE

The co-morbidities associated with epilepsy include cognitive, behavioral and emotional difficulties. Those with epilepsy are at increased risk for depression, anxiety, sleep disturbances and cognitive impairment (reviewed in 73). Cognitive impairments include problems with memory, verbal fluency, and executive function.7, 74 Approximately 70% of patients with mTLE have problems with memory function, which represents the most common cognitive impairment in this group.

Neurons generated during epileptogenic insults may impact learning in several ways, including interference with normal network function caused by aberrantly integrated neurons (Figure 3). This idea is supported by the finding that inhibition of seizure-induced neurogenesis with valproic acid (acting as an HDAC inhibitor) protects epileptic animals from deficits in hippocampal-dependent object recognition.75 Alternatively, suppression of neurogenesis during chronic epilepsy could interfere with learning and memory.34

Depression is another important co-morbidity in epilepsy (reviewed in 76). Adult neurogenesis is unlikely related to the development of depression per se, but some studies suggest that the production of DGCs is necessary for adequate response to antidepressants in rodent models of depression (reviewed in 77). Even more compelling is recent work suggesting that loss of adult-born DGCs leads to an anxiety phenotype.24 Thus, both cognitive and emotional behaviors have been linked to the production of adult-born DGCs. In summary, altered adult neurogenesis in the chronic epileptic state deserves further study to evaluate its potential role in the development of mTLE and its associated co-morbidities.

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Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

All Jasper's Basic Mechanisms of the Epilepsies content, except where otherwise noted, is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported license, which permits copying, distribution and transmission of the work, provided the original work is properly cited, not used for commercial purposes, nor is altered or transformed.

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