This is an open access publication, available online and distributed under the terms of a Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International licence (CC BY-NC-ND 4.0), a copy of which is available at https://creativecommons.org/licenses/by-nc-nd/4.0/. Subject to this license, all rights are reserved.
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies. 5th edition. New York: Oxford University Press; 2024. doi: 10.1093/med/9780197549469.003.0025
Abstract
Epilepsy is a lifelong, devastating disease that affects all ages. Epileptic seizures generate abnormal adult-born granule cells (abGCs) in the dentate gyrus, which can contribute to the development of epilepsy and comorbidities. In this chapter, we present the characteristic features and potential significance of abGC abnormalities: increased proliferation and subsequent reduction of neural progenitors, persistent hilar basal dendrites, sprouting of mossy fibers, production of hilar ectopic granule cells, and dispersion of granule cells. We also describe several key molecules that regulate seizure-induced aberrant neurogenesis. We then discuss the role of reactive astrocytes and microglia in each step of hippocampal neurogenesis during the epileptogenesis. Finally, we review the crucial findings regarding the functional implications of abnormal abGCs in epileptogenesis and summarize comorbid illnesses such as cognitive impairment and mood disturbances. Seizure-generated abGCs represent an attractive target for treating epilepsy and associated psychiatric dysfunction. Therefore, developing novel and selective antiepileptic drugs will require more basic research on the molecular mechanisms governing aberrant hippocampal neurogenesis, as well as exploiting human and non-human primate models.
Concept of Epileptogenesis
Acquired epilepsy may develop after a severe brain insult such as traumatic brain injury or status epilepticus (SE) (Pitkanen et al., 2015). After the epileptogenic injury, the normal brain transforms into an epileptic brain by poorly understood changes set in motion by the injury. Abnormalities in adult-born granule cells (abGCs) have been studied as a contributing factor. The dentate gyrus in the hippocampus—a key brain structure involved in mesial temporal lobe epilepsy (mTLE)—creates adult-born granule cells (abGCs) throughout life (Altman and Das, 1965; Ming and Song, 2005). abGCs are proposed to serve several beneficial functions, including learning and memory (Braun and Jessberger, 2014). After a severe brain injury, acute seizures trigger profound cellular and morphological changes on abGCs, including increased proliferation of progenitor cells and hilar basal dendrites, sprouting of mossy fibers, and ectopic migration of granule cells (Jessberger and Parent, 2015; Chen et al., 2020). This progression raises the question of whether seizure-induced neurogenesis is epileptogenic. Here we present the latest findings regarding the abGC abnormalities observed in various epilepsy models. We describe the molecules controlling aberrant new neuron maturation, the role of glial cells in modulating aberrant neurogenesis, and the functional implications of aberrant abGCs in epilepsy and associated neuropsychiatric conditions. We end with a discussion of the challenges and future perspectives of targeting aberrant neurogenesis to prevent epilepsy and associated comorbidities.
Morphological Changes of Adult-Born Granule Cells in Epilepsy
A wide range of brain insults can lead to acquired epilepsy (Pitkanen et al., 2015). Common cellular abnormalities among many of these injuries are altered proliferation, migration, and morphological changes in hippocampal granule cells. Interestingly, abnormal granule cells are characteristic of animal models of mTLE and of resected tissue from patients with mTLE. A summary of the seizure-induced morphological changes associated with abGCs in animal models of mTLE is shown in Figure 25–1.

Figure 25–1.
SE-induced changes in adult-born granule cells (abGC). Commonly observed morphological and migration abnormalities in abGCs that contribute to the development of spontaneous recurrent seizures (SRS) and related comorbidities. Image credit: BioRender. (more...)
A dramatic and prolonged increase in proliferation of adult hippocampal neural progenitor cells was first observed in a systemic chemoconvulsant model of epilepsy in rats (Parent et al., 1997). After SE is induced by the cholinergic agonist pilocarpine, there is a rapid increase in proliferation of neural progenitors, followed by an increase in dentate neurogenesis starting a few days after SE, and a return to baseline by 27 days after the pilocarpine treatment (Parent et al., 1997). This phenomenon has been observed in several models of acute seizures, including systemic administration of kainic acid (Bengzon et al., 1997), single unilateral intracerebroventricular (i.c.v.) injection of kainic acid (Gray and Sundstrom, 1998), and hippocampal kindling stimulation (Bengzon et al., 1997). Since these early reports, more convulsant drugs (e.g., pentylenetetrazol, flurothyl) have been found to increase abGC neurogenesis (Jiang et al., 2003; Park et al., 2006; Ferland et al., 2002). A common feature of these models is that seizures appear to mediate a dose-dependent effect on neurogenesis (Cha et al., 2004), although spontaneous seizures in the tetanus-toxin model of epilepsy are associated with increased neurogenesis even though SE does not occur in this model (Jiruska et al., 2013).
Despite this acute increase in proliferation and neurogenesis, neurogenesis generally decreases in chronic epilepsy (Hattiangady et al., 2004; Huttmann et al., 2003; Neuberger et al., 2017; Fu et al., 2019), albeit there is one paper showing a similar level of neurogenesis in epileptic female rats up until 1 year after kainic acid injection (Jessberger et al., 2007b). One proposed explanation for the early increase and later decrease is that some populations of neural stem cells may have a finite capacity to produce new neurons after excessive stimulation (Sierra et al., 2015). Recent reports suggest that in the young brain, a population of short-term neural stem cells divide rapidly to generate neurons and deplete themselves (Ibrayeva et al., 2021). Other studies suggest that the pro-activation factor ASCL1 supports heterogeneity in stem cell behavior, allowing a subset of neural stem cells to return to quiescence (Urban et al., 2016; Harris et al., 2021). We speculate that similar mechanisms may control pathological neurogenesis. Future research might employ single-cell transcriptomics, modeling, and label retention analyses to evaluate heterogeneity of new neurons after SE.
In addition to increases in proliferation and neurogenesis, abGCs undergo several distinct morphological and migratory changes, including formation of hilar basal dendrites. Basal dendrites are transiently expressed in rats during postnatal development, but granule cells of adult rats lack them; however, basal dendrites appear on granule cells of adult rats as a consequence of SE induced by pilocarpine, kainic acid, or in kindling models (Ribak et al., 2000; Spigelman et al., 1998), similar to the basal dendrites of granule cells in the brains of adult epileptic humans (Franck et al., 1995). It has been suggested that their occurrence may provide an additional basis for recurrent excitation (Ribak et al., 2000). Although morphological studies have shown that these hilar basal dendrites have synapses, little is known about their functional properties or the intrinsic and network properties of the granule cells that possess these aberrant dendrites. Recent characterization of the cellular and network properties of granule cells with hilar basal dendrites suggest that the enhanced excitability of hilar basal dendrites, combined with the altered intrinsic and network properties of granule cells, may contribute to excitability in the epileptic dentate gyrus (Kelly and Beck, 2017; Althaus et al., 2019).
The spouting of granule cell axons, known as mossy fibers, is also commonly observed in the dentate gyrus of humans with epilepsy and in experimental models (Sutula and Dudek, 2007). In rodent models of mTLE, visualization of zinc by Timm staining reveals significant increase of mossy fiber sprouting (MFS) in the dentate inner molecular layer. Mossy fibers synapse onto the apical dendrites of neighboring dentate granule cells, creating a functional excitatory feedback loop, with a minority of sprouted fibers synapsing with interneurons (Buckmaster et al., 2002; Scharfman et al., 2003). The role of MFS in epileptogenesis remains controversial; not every dentate granule cell contributes to MFS (Buckmaster and Dudek, 1999), and it is not known what influences a cell to participate. To address this, one study employed the synaptophysin gene fused to yellow fluorescent protein to label actively dividing neural progenitors; the researchers found that both neonatal and abGCs contribute to MFS in the rat pilocarpine model of mTLE (Althaus et al., 2016, Scharfman et al., 2000). Further work is needed to determine whether both populations contribute similarly on the abnormal network and hyperexcitability that contributes to epilepsy. Additionally, it remains an open question whether specific populations of dentate granule cells receive recurrent mossy fiber innervation.
One of these populations may be hilar ectopic granule cells (EGCs), which have been shown to receive mossy fiber inputs after an epileptogenic insult in rodent models of epilepsy (Parent et al., 1997; Dashtipour et al., 2001; Pierce et al., 2005; Scharfman and Pierce, 2012). Similar ectopically located granule-like neurons appear in the epileptic human hippocampus (Parent et al., 2006; Houser, 1990). Recordings from EGCs have found subtle changes in intrinsic excitability, such as hyperpolarized resting membrane potentials, which may alter network dynamics (Scharfman et al., 2000; Zhan and Nadler, 2009; Althaus et al., 2015). These EGCs also receive a greater proportion of excitatory inputs than normal dentate GCs in a rat mTLE model (Zhan et al., 2010; Pierce et al., 2011). While mounting evidence suggests that aberrant morphology/migration of abGCs can promote abnormal network function leading to seizures, studies using rodent mTLE models have reported contradictory findings: some suggesting that newborn neurons in the granule cell layer may be protective (Iyengar et al., 2015; Jain et al., 2019) and others suggesting it is pathological (discussed below). Moreover, complicating the matter is that newborn granule neurons born in the epileptic brain are heterogeneous as some cells exhibit elevated excitatory synaptic inputs, while others show reduced excitability (Jakubs et al., 2006). These discrepancies may occur because aberrant neurons contribute to seizures, but not all new neurons are aberrant. A goal for future studies will be to identify the mechanisms that distinguish pathological from healthy new neurons.
A contributing factor to ectopic migration of granule cell precursors is dispersion of granule neurons, another well-known pathological abnormality in epilepsy (Thom, 2014; Blumcke et al., 2009). The chemokine CXCL12 and its receptor CXCR4, and the extracellular matrix protein reelin, have been suggested to be involved in regulating granule cell dispersion and the placement of abGCs (Schultheiss et al., 2013; Haas and Frotscher, 2010; Muller et al., 2009b). Interestingly, in postnatal mouse subgranular zone progenitors, conditional deletion of the reelin adaptor protein disabled-1 results in abnormal dendritic development, ectopic migration, and altered seizure threshold, but was not sufficient to generate spontaneous seizures (Korn et al., 2016). These studies highlight the morphological abnormalities and migration changes of aberrant abGCs. However, we do not know which of these changes is strictly required for disrupting the hippocampal circuitry and promoting epileptogenesis—another topic for future studies.
Molecular Regulators of Aberrant Neurogenesis in Epilepsy
Investigating the genetic and molecular regulators that distinguish pathological from healthy new neurons is a route to therapeutically targeting aberrant neurogenesis in epilepsy. Early work from our lab showed that the antiseizure drug valproic acid, also a histone deacetylase (HDAC) inhibitor, suppressed aberrant neurogenesis and prevented seizure-induced cognitive impairment in rats treated with kainic acid; HDAC-dependent gene expression also normalized (Jessberger et al., 2007a). One well-studied transcription factor that recruits HDACs1/2 to repress neuronal genes in non-neuronal cells is REST (Repressor Element 1-Silencing Transcription Factor)/NRSF (Neural Restrictive Silencing Factor) (Schoenherr and Anderson, 1995; Palm et al., 1998; Ballas et al., 2005). REST is consistently upregulated in epilepsy patients and in animal models of epilepsy, and various laboratories are studying its contribution to epileptogenesis (Butler-Ryan and Wood, 2021). In addition to REST regulating genes coding for proteins involved in neuronal excitation and inhibition, including potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1(HCN1) and (potassium-chloride cotransporter (KCC2), it is also clear that REST itself is under regulation by microRNAs (miRNAs), which themselves contribute to the activation of neural stem and progenitor cells following SE (Garriga-Canut et al., 2006; McClelland et al., 2011; McClelland et al., 2014). Two of the most studied miRNAs in adult neurogenesis are miR-9 and miR-124, shown to be critical in neuronal fate determination and proliferation, respectively. Proliferation and subsequent differentiation of neural progenitors can be also influenced by Wnt signaling, which is reported to be enhanced after seizure activity (Varela-Nallar and Inestrosa, 2013; Madsen et al., 2003; Rubio et al., 2017; Huang et al., 2015). Moreover, when the kainic acid–induced β-catenin increase was suppressed by siRNA injection, the proliferation of progenitors was markedly reduced (Qu et al., 2017), suggesting a role of Wnt/β-catenin signaling in seizure-induced aberrant neurogenesis.
Studies of the role of REST, miRNAs, Wnt, and HDACs in epileptogenesis highlight the importance of transcriptional networks in controlling early epileptogenesis. In animal models of epilepsy, the selection of species, variability of epilepsy models, different brain regions, and model methods may affect transcriptional expression profiles. To address this, an epilepsy microarray consortium created epileptic rats using four different models (systemic pilocarpine or kainic acid, electrical stimulation, and amygdala kindling) and performed DNA microarray analysis of laser-captured dentate granule cells (Dingledine et al., 2017). One day after SE, only 73 out of 1,638 transcripts (4.5%) were differentially expressed across multiple labs and models, reinforcing the power of a consortium approach for the goal of identifying differential expressed transcripts in a laboratory- and model-independent manner.
Although such studies, as well as recent bulk RNA sequencing approaches, provide important information about large-scale changes in gene expression, only relatively minor transcriptomic changes have been identified because bulk RNA processing may dilute the signal by averaging gene expression across all cell types. To investigate how individual subtypes neurons are affected in epilepsy, one recent study examined mTLE by single nucleus RNA sequencing (snRNA-seq) from nonepileptic and epileptic human temporal cortex (Pfisterer et al., 2020). This study reported that several subclasses of principal neurons and GABAergic interneurons were substantially affected, and identified transcriptomic changes enriched in genes associated with epilepsy, such as genes associated with neurotransmission. Another major category of differentially expressed genes in epilepsy was associated with changes in neuronal morphology and brain development. Because all the patients in this study had mTLE of neurodevelopmental origin, it will be interesting in future studies to determine whether some of the dysregulated genes are involved in aberrant neurogenesis.
Glial Control of Aberrant Neurogenesis in Epilepsy
Acute seizures trigger strong and long-lasting activation of glial cells, which can interact with nearby adult neural stem cells (Vezzani et al., 2015). Following SE, microglia can modulate multiple stages of adult hippocampal neurogenesis, such as proliferation, migration, or maturation of neural progenitors (Luo et al., 2016a; Cho and Hsieh, 2016; Victor and Tsirka, 2020). Specifically, microglia activated from self-DNA originated from excitotoxic dead cells can inhibit the proliferative activity of neural stem cells in the epileptic hippocampus via the secretion of tumor necrosis factor (Matsuda et al., 2015). Although microglia inhibit proliferation of neural progenitors, they can promote migration and maturation of newborn neurons. When microglial activation was suppressed in epileptic rats by minocycline administration, the number of, and the total dendritic length of, hilar doublecortin (DCX)-expressing neuroblasts were significantly decreased (Yang et al., 2010). Production of DCX-expressing neuroblasts was also reduced by another pharmacological block to microglial activation: injecting neutralizing antibodies to C-X3-C Motif Chemokine Receptor 1 (CX3CR1), a receptor primarily expressed in microglia (Ali et al., 2015). Similarly, inducible microglial ablation mediated by diphtheria toxin receptor (iDTR) decreased the number of DCX+ cells in the dentate gyrus, a result that was also reproduced in microglial P2Y12 purinergic receptor knockout mice (Mo et al., 2019). Additionally, blocking P2Y12-mediated microglial activation decreased dendritic projections in newborn neurons (Mo et al., 2019), suggesting that microglia influence maturation of newborn neurons. Considering that phagocytosis is a primary role of microglia, researchers tried to demonstrate that microglia help clear newly generated cells. Interestingly, neuronal hyperexcitability in epileptic hippocampus can perturb extracellular ATP microgradients, impairing efficient microglial phagocytosis of apoptotic cells in the subgranular zone (Abiega et al., 2016). This observation was further supported as a prevention of microglial function by minocycline treatment, which impaired the ability of microglia to engulf cells, and increased the survival of hilar EGCs (Luo et al., 2016b).
While astrocytic activation in epilepsy and astrocytic control of physiologic hippocampal neurogenesis are well-known (Thom, 2014; Sultan et al., 2015), strikingly little is known about how astrocytes can affect hippocampal neurogenesis in the epileptic brain. One study demonstrated that inhibition of reactive astrocytosis by fluorocitrate injection failed to induce significant differences in seizure-induced aberrant neurogenesis, such as the production of hilar DCX+ cells (Yang et al., 2010). However, morphologically, basal dendrites of abGCs are reported to contact astrocytic processes in epileptic rats (Shapiro et al., 2005), suggesting potential interactions between these cells. Since activated astrocytes under epileptic conditions can modulate various cell types in multiple ways (Coulter and Steinhauser, 2015), further investigation is required to reveal how astrocytes contribute to seizure-induced aberrant hippocampal neurogenesis.
Functional Roles of Adult Hippocampal Neurogenesis in Acute and Chronic Phase of Epilepsy
The Role of Normal Newborn Granule Neurons in Generation of Acute Seizures
The role of adult hippocampal neurogenesis in generation of seizures is a long-lasting, essential question. abGCs have been reported to innervate local GABAergic interneurons, forming inhibitory circuitry in the dentate gyrus (Drew et al., 2016). Blocking adult hippocampal neurogenesis by focal X irradiation or transgenic glial fibrillary acidic protein (GFAP)-thymidine kinase (TK) mice increased activity of the hippocampal network (Lacefield et al., 2012). In addition, these methods of blocking neurogenesis resulted in longer seizures after kainic acid administration (Iyengar et al., 2015), supporting an inhibitory role for abGCs. Conversely, when newborn neuronal population was increased in Bax knockout mice, the duration of pilocarpine-induced acute seizures was significantly less than in control mice (Jain et al., 2019). Taken together, these studies support the dentate gate hypothesis, in which normal newborn hippocampal neurons interfere with progression of acute seizures.
The Role of Newborn Granule Neurons in Epileptogenesis
Adult hippocampal neurogenesis clearly inhibits generation of acute seizures; however, the impact of adult neurogenesis on the development of epilepsy is more complicated, given that epileptogenesis involves diverse cellular changes that cause complex rewiring of hippocampal circuitry. Many efforts have been made to find whether seizure-induced aberrant hippocampal neurogenesis is sufficient or necessary in epileptogenesis (Table 25–1). Several studies using genetic, chemogenetic, and pharmacologic approaches have demonstrated sufficiency of abnormal newborn neurons in formation of chronic seizures (Pun et al., 2012; Lybrand et al., 2021; Sakai et al., 2018). For example, selective deletion of phosphatase and tensin homolog (PTEN) in newborn granule cells resulted in hypertrophic, ectopic cells with persistent basal dendrites, a characteristic feature of mTLE (Pun et al., 2012). Interestingly, only 9% abnormality among granule cells was required for spontaneous seizures to develop (Pun et al., 2012). In line with this report, chemogenetic activation of abGCs using retroviral hM3Dq within 2 weeks after birth promoted hilar ectopic migration and spontaneous epileptic seizures in animal models (Lybrand et al., 2021). Moreover, induction of hilar ectopic granule cells by prenatal valproic acid exposure also increased susceptibility to seizures mediated by kainic acid (Sakai et al., 2018), reinforcing the importance of abnormal granule cells in epilepsy.

Table 25–1
Functional Implications of Adult Hippocampal Neurogenesis in Epilepsy.
More extensive research has been carried out to gauge the necessity of adult neurogenesis during epileptogenesis, using rodent models of epilepsy. Ever since initial pharmacological studies showed that inhibition of adult hippocampal neurogenesis after pilocarpine-induced SE reduced the frequency of SRS (Jung et al., 2004, 2006), various transgenic mouse models have been used that can selectively ablate adult hippocampal neurogenesis, demonstrating the contribution of aberrant neurogenesis to the formation of chronic epilepsy (Cho et al., 2015; Hosford et al., 2016, 2017). Specifically, removal of proliferating newly generated cells using nestin-TK mice before acute seizures successfully reduced SRS frequency for almost 1 year (Cho et al., 2015). iDTR-mediated ablation of hippocampal newborn neurons using a pilocarpine model similarly modified the disease in chronic epilepsy (Hosford et al., 2016, 2017). Furthermore, recent advances in designer receptors exclusively activated by designer drugs (DREADDs) provided new opportunities to modulate neuronal activity without removing the cells from the brain. Chemogenetic silencing of adult-generated dentate granule cells that express hM4Di at maturity reversibly decreased the frequency of epileptic spikes and SRS triggered by clozapine N-oxide (CNO) administration (Zhou et al., 2019). However, when acute seizures were induced after retroviral hM4Di injections and then hM4Di-expressing neurons were silenced 6 weeks later by CNO, the duration of SRS increased, but their frequency did not change (Lybrand et al., 2021). Instead, the authors found that blocking newborn cells within 2 weeks of birth was critical to alleviate SRS frequency and SE-induced morphological abnormalities such as hilar ectopic migration and shifted primary dendritic angle, as well as miswiring of the dentate circuit. Although studies suggest overall that aberrant hippocampal neurogenesis is required for development of epilepsy, reducing neurogenesis does not always mitigate chronic seizures, depending on the epilepsy models used and the target cellular age relative to SE onset (Raedt et al., 2007; Pekcec et al., 2008, 2011; Brulet et al., 2017; Zhu et al., 2017). Moreover, the extent to which aberrant neurogenesis is suppressed, or the influence of extrahippocampal inputs, may be also important as sustained inhibition of neurogenesis after SE only induced transient SRS reduction (Varma et al., 2019). Therefore, treating mTLE by modulating epileptogenesis will require thorough exploration of additional factors that help regulate seizure-induced aberrant hippocampal neurogenesis.
Role of Aberrant Neurogenesis in Epilepsy-Associated Comorbidities
As the latest guideline for epilepsy classification recommends describing epilepsy-associated comorbidities (Scheffer et al., 2017), it is worth discussing the impact of seizure-induced aberrant hippocampal neurogenesis on neuropsychiatric illnesses. Patients with mTLE often suffer from cognitive decline and mood disorders such as depression and anxiety (Lin et al., 2012), which are all well-known to be associated with the fundamental function of the hippocampus. Animal studies can faithfully recapitulate these behavioral deficits; various mTLE models have produced spatial memory impairment, depression-like behavior, and heightened anxiety (Jessberger et al., 2007a; Groticke et al., 2008; Pekcec et al., 2008; Mazarati et al., 2009; Muller et al., 2009a; Liu et al., 2013; Cho et al., 2015; Park et al., 2020).
To assess whether seizure-induced abnormal granule neurons play a role in psychiatric comorbidities, researchers have manipulated adult neurogenesis. For example, pharmacologic treatment with valproic acid reduced the number of proliferating progenitors and the formation of hilar basal dendrites in newborn neurons, mitigating seizure-associated cognitive impairment (Jessberger et al., 2007a). Moreover, endoneuraminidase administration also suppressed seizure-induced abnormal neurogenesis and prevented spatial memory loss (Pekcec et al., 2008). A genetic ablation of adult neurogenesis before acute seizures normalized hippocampus-dependent cognitive deficits in chronic epilepsy (Cho et al., 2015). In contrast, another study used a DNA methylating agent to nonspecifically kill neural stem cells, with no benefit to performance on the Morris water maze task (Zhu et al., 2018). Finally, observation of SRS in mice overexpressing amyloid precursor protein showed a close correlation between the biphasic fluctuation of abnormal hippocampal neurogenesis and memory impairment, which mimics the epileptogenesis in mTLE (Fu et al., 2019). Together, these reports demonstrate that the seizure-induced aberrant neurogenesis can contribute to epilepsy-associated cognitive impairment.
In contrast, there is no definitive evidence that aberrant neurogenesis affects epilepsy-associated mood disorders such as depression and anxiety. However, modulation of a few crucial molecules in adult neurogenesis may give a hint. When fosB, which can promote proliferation of neural progenitors, was knocked out in the whole animal, depressive behavior and increased anxiety manifested (Ohnishi et al., 2011). FosB knockout mice further exhibited SRS and abnormal hippocampal neurogenesis, including decreased proliferation and increased ectopic migration of newborn cells in both normal and KA-treated groups (Yutsudo et al., 2013), suggesting that fosB contributes to epilepsy-associated mood disorders via aberrant hippocampal neurogenesis. Another example is TrkB, a receptor for brain-derived neurotrophic factor. TrkB deletion in adult hippocampal progenitors resulted in reduced dendritic arborization and anxiety-like behavior (Bergami et al., 2008). Moreover, an elaborate chemical-genetic approach to inhibit TrkB activation after SE altered epileptogenesis and epilepsy-associated anxiety behavior (Liu et al., 2013). Collectively, these data support the idea that aberrant hippocampal neurogenesis impacts epilepsy-related psychiatric comorbidities.
Conclusions and Future Perspectives
Seizure-induced aberrant hippocampal neurogenesis is a multistep process dynamically influenced by many different cell types in the hippocampus and other brain regions. While newborn granule cells after acute seizures are generally thought to promote the development of epilepsy and psychiatric comorbidities, the detailed molecular mechanisms at the cellular and network levels remain to be elucidated. Based on the anatomical location of adult-generated granule neurons in chronic epilepsy, heterogeneity of seizure-induced granule cells is anticipated. With the advent of single-cell sequencing approaches, it may be possible to distinguish normal and abnormal adult-generated granule cells after SE, which can identify specific targets for epileptogenesis. Furthermore, recent studies using rabies virus-mediated connectivity tracing demonstrated remarkably complex inputs to the adult-generated granule cells in the epileptic brain, controllable by newborn neuron activity (Zhou et al., 2019; Lybrand et al., 2021). Thus, targeting inputs from CA3 pyramidal neurons or entorhinal cortex may provide a new way to instruct seizure-generated newborn neurons to form normal rather than epileptogenic circuits. Future studies on sophisticated mechanisms of seizure-induced aberrant hippocampal neurogenesis will guide us to develop a promising target for intervention in the cure of epilepsy and its comorbidities.
A challenge is translating work from rodent models of mTLE to human patients. In epileptic patients, it has been reported that seizures enhance the level of neurogenesis in some cases, particularly in young patients (Blumcke et al., 2001), but not in others (Peng and Bonaguidi, 2018; Zhong et al., 2016; Siebzehnrubl and Blumcke, 2008; Sorrells et al., 2018). The discrepancies among these human studies may be due to differences in specimens, fixation methods, and antibodies used to detect the neuronal progenitors and immature neurons (Moreno-Jimenez et al., 2019; Boldrini et al., 2018; Lucassen et al., 2020). Another factor is the time interval from the initial diagnosis of epilepsy to the time of surgery. These are important issues to consider when comparing conclusions on adult human neurogenesis in epileptogenesis (Bao and Swaab, 2018). Interestingly, a recent study suggests that while adult neurogenesis in epilepsy patients occurs at a low level, there was a similarity in the morphology, distribution, and epilepsy-induced alterations between human PSA-NCAM+ and rodent newly generated granule cells, suggesting that they may share some similar properties related to their immaturity (Seki et al., 2019). Additional research is needed to address the exact function, developmental state, and pathology of PSA-NCAM+ cells in the adult human hippocampus. Non-human primate models of epilepsy, such as the natural baboon model for genetic generalized epilepsy with photosensitivity (Szabo and Salinas, 2021; Croll et al., 2019), could be used to evaluate adult neurogenesis, with results being readily translated to humans due to phylogenetic proximity.
Substantial progress has been made in the field of adult neurogenesis over the past decade, especially its mechanisms and functions in epileptogenesis, but there is still much to learn about how to suppress aberrant new neurons and promote healthy new neurons. More basic research is needed to develop tools to identify and measure adult neurogenesis in animals and humans, and to selectively target molecular and cellular processes that govern aberrant neurogenesis in epileptogenesis.
Acknowledgments
We thank the members of the Cho and Hsieh labs for insightful discussions and Aline Mckenzie for editing support. This work was supported by grants from the National Research Foundation of Korea (NRF) (2019R1A2C1003958, 2021R1A4A5028966 to KOC). This work was also supported by grants from the National Institutes of Health (NIH) (R01NS124855, R01NS113516, U01DA054170 to JH), a UT System Brain Health Pilot Project Award (to JH), and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation and the Semmes Foundation (to JH).
Disclosure Statement
The authors declare no relevant conflicts.
References
- Abiega, O., Beccari, S., Diaz–aparicio, I., Nadjar, A., Laye, S., Leyrolle, Q., Gomez–nicola, D., Domercq, M., Perez–samartin, A., Sanchez–zafra, V., Paris, I., Valero, J., Savage, J. C., Hui, C. W., Tremblay, M. E., Deudero, J. J., Brewster, A. L., Anderson, A. E., Zaldumbide, L., Galbarriatu, L., Marinas, A., Vivanco, M., Matute, C., Maletic–savatic, M., Encinas, J. M. & Sierra, A. 2016. Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling. PLoS Biol, 14, e1002466. [PMC free article: PMC4881984] [PubMed: 27228556]
- Ali, I., Chugh, D. & Ekdahl, C. T. 2015. Role of fractalkine–CX3CR1 pathway in seizure–induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain. Neurobiol Dis, 74, 194–203. [PubMed: 25461978]
- Althaus, A. L., Moore, S. J., Zhang, H., Du, X., Murphy, G. G. & Parent, J. M. 2019. Altered Synaptic Drive onto Birthdated Dentate Granule Cells in Experimental Temporal Lobe Epilepsy. J Neurosci, 39, 7604–7614. [PMC free article: PMC6750946] [PubMed: 31270158]
- Althaus, A. L., Sagher, O., Parent, J. M. & Murphy, G. G. 2015. Intrinsic neurophysiological properties of hilar ectopic and normotopic dentate granule cells in human temporal lobe epilepsy and a rat model. J Neurophysiol, 113, 1184–94. [PMC free article: PMC4329435] [PubMed: 25429123]
- Althaus, A. L., Zhang, H. & Parent, J. M. 2016. Axonal plasticity of age–defined dentate granule cells in a rat model of mesial temporal lobe epilepsy. Neurobiol Dis, 86, 187–96. [PMC free article: PMC4733350] [PubMed: 26644085]
- Altman, J. & Das, G. D. 1965. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol, 124, 319–35. [PubMed: 5861717]
- Ballas, N., Grunseich, C., Lu, D. D., Speh, J. C. & Mandel, G. 2005. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell, 121, 645–657. [PubMed: 15907476]
- Bao, A. M. & Swaab, D. F. 2018. The art of matching brain tissue from patients and controls for postmortem research. Handb Clin Neurol, 150, 197–217. [PubMed: 29496142]
- Bengzon, J., Kokaia, Z., Elmer, E., Nanobashvili, A., Kokaia, M. & Lindvall, O. 1997. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A, 94, 10432–7. [PMC free article: PMC23380] [PubMed: 9294228]
- Bergami, M., Rimondini, R., Santi, S., Blum, R., Gotz, M. & Canossa, M. 2008. Deletion of TrkB in adult progenitors alters newborn neuron integration into hippocampal circuits and increases anxiety–like behavior. Proc Natl Acad Sci U S A, 105, 15570–5. [PMC free article: PMC2557028] [PubMed: 18832146]
- Blumcke, I., Kistner, I., Clusmann, H., Schramm, J., Becker, A. J., Elger, C. E., Bien, C. G., Merschhemke, M., Meencke, H. J., Lehmann, T., Buchfelder, M., Weigel, D., Buslei, R., Stefan, H., Pauli, E. & Hildebrandt, M. 2009. Towards a clinico–pathological classification of granule cell dispersion in human mesial temporal lobe epilepsies. Acta Neuropathol, 117, 535–44. [PubMed: 19277686]
- Blumcke, I., Schewe, J. C., Normann, S., Brustle, O., Schramm, J., Elger, C. E. & Wiestler, O. D. 2001. Increase of nestin–immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early–onset temporal lobe epilepsy. Hippocampus, 11, 311–21. [PubMed: 11769312]
- Boldrini, M., Fulmore, C. A., Tartt, A. N., Simeon, L. R., Pavlova, I., Poposka, V., Rosoklija, G. B., Stankov, A., Arango, V., Dwork, A. J., Hen, R. & Mann, J. J. 2018. Human Hippocampal Neurogenesis Persists throughout Aging. Cell Stem Cell, 22, 589–599 e5. [PMC free article: PMC5957089] [PubMed: 29625071]
- Braun, S. M. & Jessberger, S. 2014. Adult neurogenesis: mechanisms and functional significance. Development, 141, 1983–6. [PubMed: 24803647]
- Brulet, R., Zhu, J. F., Aktar, M., Hsieh, J. & Cho, K. O. 2017. Mice with conditional NeuroD1 knockout display reduced aberrant hippocampal neurogenesis but no change in epileptic seizures. Experimental Neurology, 293, 190–198. [PMC free article: PMC5503142] [PubMed: 28427858]
- Buckmaster, P. S. & Dudek, F. E. 1999. In vivo intracellular analysis of granule cell axon reorganization in epileptic rats. J Neurophysiol, 81, 712–21. [PubMed: 10036272]
- Buckmaster, P. S., Zhang, G. F. & Yamawaki, R. 2002. Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit. J Neurosci, 22, 6650–8. [PMC free article: PMC6758164] [PubMed: 12151544]
- Butler–ryan, R. & Wood, I. C. 2021. The functions of repressor element 1–silencing transcription factor in models of epileptogenesis and post–ischemia. Metab Brain Dis, 36, 1135–1150. [PMC free article: PMC8272694] [PubMed: 33813634]
- Cha, B. H., Akman, C., Silveira, D. C., Liu, X. & Holmes, G. L. 2004. Spontaneous recurrent seizure following status epilepticus enhances dentate gyrus neurogenesis. Brain Dev, 26, 394–7. [PubMed: 15275703]
- Chen, L., Wang, Y. & Chen, Z. 2020. Adult Neurogenesis in Epileptogenesis: An Update for Preclinical Finding and Potential Clinical Translation. Curr Neuropharmacol, 18, 464–484. [PMC free article: PMC7457402] [PubMed: 31744451]
- Cho, K. O. & Hsieh, J. 2016. Microglial TLR9: Guardians of Homeostatic Hippocampal Neurogenesis. Epilepsy Curr, 16, 39–40. [PMC free article: PMC4749116] [PubMed: 26900378]
- Cho, K. O., Lybrand, Z. R., Ito, N., Brulet, R., Tafacory, F., Zhang, L., Good, L., Ure, K., Kernie, S. G., Birnbaum, S. G., Scharfman, H. E., Eisch, A. J. & Hsieh, J. 2015. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat Commun, 6, 6606. [PMC free article: PMC4375780] [PubMed: 25808087]
- Coulter, D. A. & Steinhauser, C. 2015. Role of astrocytes in epilepsy. Cold Spring Harb Perspect Med, 5, a022434. [PMC free article: PMC4355248] [PubMed: 25732035]
- Croll, L., Szabo, C. A., Abou–madi, N. & Devinsky, O. 2019. Epilepsy in nonhuman primates. Epilepsia, 60, 1526–1538. [PMC free article: PMC6779127] [PubMed: 31206636]
- Dashtipour, K., Tran, P. H., Okazaki, M. M., Nadler, J. V. & Ribak, C. E. 2001. Ultrastructural features and synaptic connections of hilar ectopic granule cells in the rat dentate gyrus are different from those of granule cells in the granule cell layer. Brain Res, 890, 261–71. [PubMed: 11164792]
- Dingledine, R., Coulter, D. A., Fritsch, B., Gorter, J. A., Lelutiu, N., Mcnamara, J., Nadler, J. V., Pitkanen, A., Rogawski, M. A., Skene, P., Sloviter, R. S., Wang, Y., Wadman, W. J., Wasterlain, C. & Roopra, A. 2017. Transcriptional profile of hippocampal dentate granule cells in four rat epilepsy models. Sci Data, 4, 170061. [PMC free article: PMC5423390] [PubMed: 28485718]
- Drew, L. J., Kheirbek, M. A., Luna, V. M., Denny, C. A., Cloidt, M. A., Wu, M. V., Jain, S., Scharfman, H. E. & Hen, R. 2016. Activation of local inhibitory circuits in the dentate gyrus by adult–born neurons. Hippocampus, 26, 763–78. [PMC free article: PMC4867135] [PubMed: 26662922]
- Ferland, R. J., Gross, R. A. & Applegate, C. D. 2002. Increased mitotic activity in the dentate gyrus of the hippocampus of adult C57BL/6J mice exposed to the flurothyl kindling model of epileptogenesis. Neuroscience, 115, 669–83. [PubMed: 12435406]
- Franck, J. E., Pokorny, J., Kunkel, D. D. & Schwartzkroin, P. A. 1995. Physiologic and morphologic characteristics of granule cell circuitry in human epileptic hippocampus. Epilepsia, 36, 543–58. [PubMed: 7555966]
- Fu, C. H., Iascone, D. M., Petrof, I., Hazra, A., Zhang, X., Pyfer, M. S., Tosi, U., Corbett, B. F., Cai, J., Lee, J., Park, J., Iacovitti, L., Scharfman, H. E., Enikolopov, G. & Chin, J. 2019. Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model. Cell Rep, 27, 3741–3751 e4. [PMC free article: PMC6697001] [PubMed: 31242408]
- Garriga–canut, M., Schoenike, B., Qazi, R., Bergendahl, K., Daley, T. J., Pfender, R. M., Morrison, J. F., Ockuly, J., Stafstrom, C., Sutula, T. & Roopra, A. 2006. 2–Deoxy–D–glucose reduces epilepsy progression by NRSF–CtBP–dependent metabolic regulation of chromatin structure. Nat Neurosci, 9, 1382–7. [PubMed: 17041593]
- Gray, W. P. & Sundstrom, L. E. 1998. Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res, 790, 52–9. [PubMed: 9593820]
- Groticke, I., Hoffmann, K. & Loscher, W. 2008. Behavioral alterations in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainate. Exp Neurol, 213, 71–83. [PubMed: 18585709]
- Haas, C. A. & Frotscher, M. 2010. Reelin deficiency causes granule cell dispersion in epilepsy. Exp Brain Res, 200, 141–9. [PubMed: 19633980]
- Harris, L., Rigo, P., Stiehl, T., Gaber, Z. B., Austin, S. H. L., Masdeu, M. D. M., Edwards, A., Urban, N., Marciniak–czochra, A. & Guillemot, F. 2021. Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population. Cell Stem Cell, 28, 863–876 e6. [PMC free article: PMC8110946] [PubMed: 33581058]
- Hattiangady, B., Rao, M. S. & Shetty, A. K. 2004. Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis, 17, 473–90. [PubMed: 15571983]
- Hosford, B. E., Liska, J. P. & Danzer, S. C. 2016. Ablation of Newly Generated Hippocampal Granule Cells Has Disease–Modifying Effects in Epilepsy. Journal of Neuroscience, 36, 11013–11023. [PMC free article: PMC5098838] [PubMed: 27798182]
- Hosford, B. E., Rowley, S., Liska, J. P. & Danzer, S. C. 2017. Ablation of peri–insult generated granule cells after epilepsy onset halts disease progression. Sci Rep, 7, 18015. [PMC free article: PMC5740143] [PubMed: 29269775]
- Houser, C. R. 1990. Granule cell dispersion in the dentate gyrus of humans with temporal lobe epilepsy. Brain Res, 535, 195–204. [PubMed: 1705855]
- Huang, C., Fu, X. H., Zhou, D. & Li, J. M. 2015. The Role of Wnt/beta–Catenin Signaling Pathway in Disrupted Hippocampal Neurogenesis of Temporal Lobe Epilepsy: A Potential Therapeutic Target? Neurochem Res, 40, 1319–32. [PubMed: 26012365]
- Huttmann, K., Sadgrove, M., Wallraff, A., Hinterkeuser, S., Kirchhoff, F., Steinhauser, C. & Gray, W. P. 2003. Seizures preferentially stimulate proliferation of radial glia–like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. Eur J Neurosci, 18, 2769–78. [PubMed: 14656326]
- Ibrayeva, A., Bay, M., Pu, E., Jorg, D. J., Peng, L., Jun, H., Zhang, N., Aaron, D., Lin, C., Resler, G., Hidalgo, A., Jang, M. H., Simons, B. D. & Bonaguidi, M. A. 2021. Early stem cell aging in the mature brain. Cell Stem Cell, 28, 955–966 e7. [PMC free article: PMC10069280] [PubMed: 33848469]
- Iyengar, S. S., Lafrancois, J. J., Friedman, D., Drew, L. J., Denny, C. A., Burghardt, N. S., Wu, M. V., Hsieh, J., Hen, R. & Scharfman, H. E. 2015. Suppression of adult neurogenesis increases the acute effects of kainic acid. Exp Neurol, 264, 135–49. [PMC free article: PMC4800819] [PubMed: 25476494]
- Jain, S., Lafrancois, J. J., Botterill, J. J., Alcantara–gonzalez, D. & Scharfman, H. E. 2019. Adult neurogenesis in the mouse dentate gyrus protects the hippocampus from neuronal injury following severe seizures. Hippocampus, 29, 683–709. [PMC free article: PMC6640126] [PubMed: 30672046]
- Jakubs, K., Nanobashvili, A., Bonde, S., Ekdahl, C. T., Kokaia, Z., Kokaia, M. & Lindvall, O. 2006. Environment matters: synaptic properties of neurons born in the epileptic adult brain develop to reduce excitability. Neuron, 52, 1047–59. [PubMed: 17178407]
- Jessberger, S., Nakashima, K., Clemenson, G. D., JR., Mejia, E., Mathews, E., Ure, K., Ogawa, S., Sinton, C. M., Gage, F. H. & Hsieh, J. 2007a. Epigenetic modulation of seizure–induced neurogenesis and cognitive decline. J Neurosci, 27, 5967–75. [PMC free article: PMC6672253] [PubMed: 17537967]
- Jessberger, S. & Parent, J. M. 2015. Epilepsy and Adult Neurogenesis. Cold Spring Harb Perspect Biol, 7, a020677. [PMC free article: PMC4665072] [PubMed: 26552418]
- Jessberger, S., Zhao, C., Toni, N., Clemenson, G. D., JR., Li, Y. & Gage, F. H. 2007b. Seizure–associated, aberrant neurogenesis in adult rats characterized with retrovirus–mediated cell labeling. J Neurosci, 27, 9400–7. [PMC free article: PMC6673128] [PubMed: 17728453]
- Jiang, W., Wan, Q., Zhang, Z. J., Wang, W. D., Huang, Y. G., Rao, Z. R. & Zhang, X. 2003. Dentate granule cell neurogenesis after seizures induced by pentylenetrazol in rats. Brain Res, 977, 141–8. [PubMed: 12834874]
- Jiruska, P., Shtaya, A. B., Bodansky, D. M., Chang, W. C., Gray, W. P. & Jefferys, J. G. 2013. Dentate gyrus progenitor cell proliferation after the onset of spontaneous seizures in the tetanus toxin model of temporal lobe epilepsy. Neurobiol Dis, 54, 492–8. [PMC free article: PMC3635088] [PubMed: 23439313]
- Jung, K. H., Chu, K., Kim, M., Jeong, S. W., Song, Y. M., Lee, S. T., Kim, J. Y., Lee, S. K. & Roh, J. K. 2004. Continuous cytosine–b–D–arabinofuranoside infusion reduces ectopic granule cells in adult rat hippocampus with attenuation of spontaneous recurrent seizures following pilocarpine–induced status epilepticus. Eur J Neurosci, 19, 3219–26. [PubMed: 15217378]
- Jung, K. H., Chu, K., Lee, S. T., Kim, J., Sinn, D. I., Kim, J. M., Park, D. K., Lee, J. J., Kim, S. U., Kim, M., Lee, S. K. & Roh, J. K. 2006. Cyclooxygenase–2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine–induced status epilepticus. Neurobiol Dis, 23, 237–46. [PubMed: 16806953]
- Kelly, T. & Beck, H. 2017. Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus. Epilepsia, 58, 160–171. [PubMed: 27888509]
- Korn, M. J., Mandle, Q. J. & Parent, J. M. 2016. Conditional Disabled–1 Deletion in Mice Alters Hippocampal Neurogenesis and Reduces Seizure Threshold. Front Neurosci, 10, 63. [PMC free article: PMC4766299] [PubMed: 26941603]
- Lacefield, C. O., Itskov, V., Reardon, T., Hen, R. & Gordon, J. A. 2012. Effects of adult–generated granule cells on coordinated network activity in the dentate gyrus. Hippocampus, 22, 106–16. [PMC free article: PMC3282563] [PubMed: 20882540]
- Lin, J. J., Mula, M. & Hermann, B. P. 2012. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet, 380, 1180–92. [PMC free article: PMC3838617] [PubMed: 23021287]
- Liu, G., Gu, B., He, X. P., Joshi, R. B., Wackerle, H. D., Rodriguiz, R. M., Wetsel, W. C. & Mcnamara, J. O. 2013. Transient inhibition of TrkB kinase after status epilepticus prevents development of temporal lobe epilepsy. Neuron, 79, 31–8. [PMC free article: PMC3744583] [PubMed: 23790754]
- Lucassen, P. J., Toni, N., Kempermann, G., Frisen, J., Gage, F. H. & Swaab, D. F. 2020. Limits to human neurogenesis–really? Mol Psychiatry, 25, 2207–2209. [PMC free article: PMC7515796] [PubMed: 30617274]
- Luo, C., Ikegaya, Y. & Koyama, R. 2016a. Microglia and neurogenesis in the epileptic dentate gyrus. Neurogenesis (Austin), 3, e1235525. [PMC free article: PMC5120684] [PubMed: 27928548]
- Luo, C., Koyama, R. & Ikegaya, Y. 2016b. Microglia engulf viable newborn cells in the epileptic dentate gyrus. Glia, 64, 1508–17. [PubMed: 27301702]
- Lybrand, Z. R., Goswami, S., Zhu, J., Jarzabek, V., Merlock, N., Aktar, M., Smith, C., Zhang, L., Varma, P., Cho, K. O., Ge, S. & Hsieh, J. 2021. A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy. Nat Commun, 12, 1423. [PMC free article: PMC7930276] [PubMed: 33658509]
- Madsen, T. M., Newton, S. S., Eaton, M. E., Russell, D. S. & Duman, R. S. 2003. Chronic electroconvulsive seizure up–regulates beta–catenin expression in rat hippocampus: role in adult neurogenesis. Biol Psychiatry, 54, 1006–14. [PubMed: 14625142]
- Matsuda, T., Murao, N., Katano, Y., Juliandi, B., Kohyama, J., Akira, S., Kawai, T. & Nakashima, K. 2015. TLR9 signalling in microglia attenuates seizure–induced aberrant neurogenesis in the adult hippocampus. Nat Commun, 6, 6514. [PMC free article: PMC4366529] [PubMed: 25751136]
- Mazarati, A. M., Shin, D., Kwon, Y. S., Bragin, A., Pineda, E., Tio, D., Taylor, A. N. & Sankar, R. 2009. Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy. Neurobiol Dis, 34, 457–61. [PMC free article: PMC2683188] [PubMed: 19285131]
- Mcclelland, S., Brennan, G. P., Dube, C., Rajpara, S., Iyer, S., Richichi, C., Bernard, C. & Baram, T. Z. 2014. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. Elife, 3, e01267. [PMC free article: PMC4129437] [PubMed: 25117540]
- Mcclelland, S., Flynn, C., Dube, C., Richichi, C., Zha, Q., Ghestem, A., Esclapez, M., Bernard, C. & Baram, T. Z. 2011. Neuron–restrictive silencer factor–mediated hyperpolarization–activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann Neurol, 70, 454–64. [PMC free article: PMC3177145] [PubMed: 21905079]
- Ming, G. L. & Song, H. 2005. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci, 28, 223–50. [PubMed: 16022595]
- Mo, M., Eyo, U. B., Xie, M., Peng, J., Bosco, D. B., Umpierre, A. D., Zhu, X., Tian, D. S., Xu, P. & Wu, L. J. 2019. Microglial P2Y12 Receptor Regulates Seizure–Induced Neurogenesis and Immature Neuronal Projections. J Neurosci, 39, 9453–9464. [PMC free article: PMC6867812] [PubMed: 31597724]
- Moreno–jimenez, E. P., Flor–garcia, M., Terreros–roncal, J., Rabano, A., Cafini, F., Pallas–bazarra, N., Avila, J. & Llorens–martin, M. 2019. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med, 25, 554–560. [PubMed: 30911133]
- Muller, C. J., Groticke, I., Bankstahl, M. & Loscher, W. 2009a. Behavioral and cognitive alterations, spontaneous seizures, and neuropathology developing after a pilocarpine–induced status epilepticus in C57BL/6 mice. Exp Neurol, 219, 284–97. [PubMed: 19500573]
- Muller, M. C., Osswald, M., Tinnes, S., Haussler, U., Jacobi, A., Forster, E., Frotscher, M. & Haas, C. A. 2009b. Exogenous reelin prevents granule cell dispersion in experimental epilepsy. Exp Neurol, 216, 390–7. [PubMed: 19185570]
- Neuberger, E. J., Swietek, B., Corrubia, L., Prasanna, A. & Santhakumar, V. 2017. Enhanced Dentate Neurogenesis after Brain Injury Undermines Long–Term Neurogenic Potential and Promotes Seizure Susceptibility. Stem Cell Reports, 9, 972–984. [PMC free article: PMC5599224] [PubMed: 28826852]
- Ohnishi, Y. N., Ohnishi, Y. H., Hokama, M., Nomaru, H., Yamazaki, K., Tominaga, Y., Sakumi, K., Nestler, E. J. & Nakabeppu, Y. 2011. FosB Is Essential for the Enhancement of Stress Tolerance and Antagonizes Locomotor Sensitization by Delta FosB. Biological Psychiatry, 70, 487–495. [PMC free article: PMC3264950] [PubMed: 21679928]
- Palm, K., Belluardo, N., Metsis, M. & Timmusk, T. 1998. Neuronal expression of zinc finger transcription factor REST/NRSF/XBR gene. J Neurosci, 18, 1280–96. [PMC free article: PMC6792720] [PubMed: 9454838]
- Parent, J. M., Elliott, R. C., Pleasure, S. J., Barbaro, N. M. & Lowenstein, D. H. 2006. Aberrant seizure–induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol, 59, 81–91. [PubMed: 16261566]
- Parent, J. M., Yu, T. W., Leibowitz, R. T., Geschwind, D. H., Sloviter, R. S. & Lowenstein, D. H. 1997. Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci, 17, 3727–38. [PMC free article: PMC6573703] [PubMed: 9133393]
- Park, J. H., Cho, H., Kim, H. & Kim, K. 2006. Repeated brief epileptic seizures by pentylenetetrazole cause neurodegeneration and promote neurogenesis in discrete brain regions of freely moving adult rats. Neuroscience, 140, 673–84. [PubMed: 16616429]
- Park, K. M., Kim, J. E., Choi, I. Y. & Cho, K. O. 2020. Assessment of Memory Function in Pilocarpine–induced Epileptic Mice. J Vis Exp, 160. [PubMed: 32568250]
- Pekcec, A., Fuest, C., Muhlenhoff, M., Gerardy–schahn, R. & Potschka, H. 2008. Targeting epileptogenesis–associated induction of neurogenesis by enzymatic depolysialylation of NCAM counteracts spatial learning dysfunction but fails to impact epilepsy development. J Neurochem, 105, 389–400. [PubMed: 18194217]
- Pekcec, A., Lupke, M., Baumann, R., Seifert, H. & Potschka, H. 2011. Modulation of neurogenesis by targeted hippocampal irradiation fails to affect kindling progression. Hippocampus, 21, 866–76. [PubMed: 20865736]
- Peng, L. & Bonaguidi, M. A. 2018. Function and Dysfunction of Adult Hippocampal Neurogenesis in Regeneration and Disease. Am J Pathol, 188, 23–28. [PMC free article: PMC5745527] [PubMed: 29030053]
- Pfisterer, U., Petukhov, V., Demharter, S., Meichsner, J., Thompson, J. J., Batiuk, M. Y., Asenjo–martinez, A., Vasistha, N. A., Thakur, A., Mikkelsen, J., Adorjan, I., Pinborg, L. H., Pers, T. H., Von engelhardt, J., Kharchenko, P. V. & Khodosevich, K. 2020. Identification of epilepsy–associated neuronal subtypes and gene expression underlying epileptogenesis. Nat Commun, 11, 5038. [PMC free article: PMC7541486] [PubMed: 33028830]
- Pierce, J. P., Mccloskey, D. P. & Scharfman, H. E. 2011. Morphometry of hilar ectopic granule cells in the rat. J Comp Neurol, 519, 1196–218. [PMC free article: PMC3984463] [PubMed: 21344409]
- Pierce, J. P., Melton, J., Punsoni, M., Mccloskey, D. P. & Scharfman, H. E. 2005. Mossy fibers are the primary source of afferent input to ectopic granule cells that are born after pilocarpine–induced seizures. Exp Neurol, 196, 316–31. [PMC free article: PMC1431686] [PubMed: 16342370]
- Pitkanen, A., Lukasiuk, K., Dudek, F. E. & Staley, K. J. 2015. Epileptogenesis. Cold Spring Harb Perspect Med, 5, a022822. [PMC free article: PMC4588129] [PubMed: 26385090]
- Pun, R. Y., Rolle, I. J., Lasarge, C. L., Hosford, B. E., Rosen, J. M., Uhl, J. D., Schmeltzer, S. N., Faulkner, C., Bronson, S. L., Murphy, B. L., Richards, D. A., Holland, K. D. & Danzer, S. C. 2012. Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy. Neuron, 75, 1022–34. [PMC free article: PMC3474536] [PubMed: 22998871]
- Qu, Z., Su, F., Qi, X., Sun, J., Wang, H., Qiao, Z., Zhao, H. & Zhu, Y. 2017. Wnt/beta–catenin signalling pathway mediated aberrant hippocampal neurogenesis in kainic acid–induced epilepsy. Cell Biochem Funct, 35, 472–476. [PubMed: 29052243]
- Raedt, R., Boon, P., Persson, A., Alborn, A. M., Boterberg, T., Van dycke, A., Linder, B., De smedt, T., Wadman, W. J., Ben–menachem, E. & Eriksson, P. S. 2007. Radiation of the rat brain suppresses seizure–induced neurogenesis and transiently enhances excitability during kindling acquisition. Epilepsia, 48, 1952–63. [PubMed: 17555527]
- Ribak, C. E., Tran, P. H., Spigelman, I., Okazaki, M. M. & Nadler, J. V. 2000. Status epilepticus–induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry. J Comp Neurol, 428, 240–53. [PubMed: 11064364]
- Rubio, C., Rosiles–abonce, A., Trejo–solis, C., Rubio–osornio, M., Mendoza, C., Custodio, V., Martinez–lazcano, J. C., Gonzalez, E. & Paz, C. 2017. Increase Signaling of Wnt/beta–Catenin Pathway and Presence of Apoptosis in Cerebellum of Kindled Rats. CNS Neurol Disord Drug Targets, 16, 772–780. [PubMed: 28124605]
- Sakai, A., Matsuda, T., Doi, H., Nagaishi, Y., Kato, K. & Nakashima, K. 2018. Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice. Proc Natl Acad Sci U S A, 115, 4270–4275. [PMC free article: PMC5910824] [PubMed: 29610328]
- Scharfman, H. E., Goodman, J. H. & Sollas, A. L. 2000. Granule–like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure–induced neurogenesis. J Neurosci, 20, 6144–58. [PMC free article: PMC6772593] [PubMed: 10934264]
- Scharfman, H. E. & Pierce, J. P. 2012. New insights into the role of hilar ectopic granule cells in the dentate gyrus based on quantitative anatomic analysis and three–dimensional reconstruction. Epilepsia, 53 Suppl 1, 109–15. [PMC free article: PMC3920449] [PubMed: 22612815]
- Scharfman, H. E., Sollas, A. L., Berger, R. E. & Goodman, J. H. 2003. Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure–induced mossy fiber sprouting. J Neurophysiol, 90, 2536–47. [PubMed: 14534276]
- Scheffer, I. E., Berkovic, S., Capovilla, G., Connolly, M. B., French, J., Guilhoto, L., Hirsch, E., Jain, S., Mathern, G. W., Moshe, S. L., Nordli, D. R., Perucca, E., Tomson, T., Wiebe, S., Zhang, Y. H. & Zuberi, S. M. 2017. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia, 58, 512–521. [PMC free article: PMC5386840] [PubMed: 28276062]
- Schoenherr, C. J. & Anderson, D. J. 1995. The neuron–restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron–specific genes. Science, 267, 1360–3. [PubMed: 7871435]
- Schultheiss, C., Abe, P., Hoffmann, F., Mueller, W., Kreuder, A. E., Schutz, D., Haege, S., Redecker, C., Keiner, S., Kannan, S., Claasen, J. H., Pfrieger, F. W. & Stumm, R. 2013. CXCR4 prevents dispersion of granule neuron precursors in the adult dentate gyrus. Hippocampus, 23, 1345–58. [PubMed: 23929505]
- Seki, T., Hori, T., Miyata, H., Maehara, M. & Namba, T. 2019. Analysis of proliferating neuronal progenitors and immature neurons in the human hippocampus surgically removed from control and epileptic patients. Sci Rep, 9, 18194. [PMC free article: PMC6890740] [PubMed: 31796832]
- Shapiro, L. A., Korn, M. J. & Ribak, C. E. 2005. Newly generated dentate granule cells from epileptic rats exhibit elongated hilar basal dendrites that align along GFAP–immunolabeled processes. Neuroscience, 136, 823–831. [PubMed: 16344154]
- Siebzehnrubl, F. A. & Blumcke, I. 2008. Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies. Epilepsia, 49 Suppl 5, 55–65. [PubMed: 18522601]
- Sierra, A., Martin–suarez, S., Valcarcel–martin, R., Pascual–brazo, J., Aelvoet, S. A., Abiega, O., Deudero, J. J., Brewster, A. L., Bernales, I., Anderson, A. E., Baekelandt, V., Maletic–savatic, M. & Encinas, J. M. 2015. Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell, 16, 488–503. [PMC free article: PMC4443499] [PubMed: 25957904]
- Sorrells, S. F., Paredes, M. F., Cebrian–silla, A., Sandoval, K., Qi, D., Kelley, K. W., James, D., Mayer, S., Chang, J., Auguste, K. I., Chang, E. F., Gutierrez, A. J., Kriegstein, A. R., Mathern, G. W., Oldham, M. C., Huang, E. J., Garcia–verdugo, J. M., Yang, Z. & Alvarez–buylla, A. 2018. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature, 555, 377–381. [PMC free article: PMC6179355] [PubMed: 29513649]
- Spigelman, I., Yan, X. X., Obenaus, A., Lee, E. Y., Wasterlain, C. G. & Ribak, C. E. 1998. Dentate granule cells form novel basal dendrites in a rat model of temporal lobe epilepsy. Neuroscience, 86, 109–20. [PubMed: 9692747]
- Sultan, S., Li, L. Y., Moss, J., Petrelli, F., Casse, F., Gebara, E., Lopatar, J., Pfrieger, F. W., Bezzi, P., Bischofberger, J. & Toni, N. 2015. Synaptic Integration of Adult–Born Hippocampal Neurons Is Locally Controlled by Astrocytes. Neuron, 88, 957–72. [PubMed: 26606999]
- Sutula, T. P. & Dudek, F. E. 2007. Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: an emergent property of a complex system. Prog Brain Res, 163, 541–63. [PubMed: 17765737]
- Szabo, C. A. & Salinas, F. S. 2021. The baboon in epilepsy research: Revelations and challenges. Epilepsy Behav, 121, 108012. [PMC free article: PMC8238811] [PubMed: 34022622]
- Thom, M. 2014. Review: Hippocampal sclerosis in epilepsy: a neuropathology review. Neuropathol Appl Neurobiol, 40, 520–43. [PMC free article: PMC4265206] [PubMed: 24762203]
- Urban, N., Van den berg, D. L., Forget, A., Andersen, J., Demmers, J. A., Hunt, C., Ayrault, O. & Guillemot, F. 2016. Return to quiescence of mouse neural stem cells by degradation of a proactivation protein. Science, 353, 292–5. [PMC free article: PMC5321528] [PubMed: 27418510]
- Varela–nallar, L. & Inestrosa, N. C. 2013. Wnt signaling in the regulation of adult hippocampal neurogenesis. Front Cell Neurosci, 7, 100. [PMC free article: PMC3693081] [PubMed: 23805076]
- Varma, P., Brulet, R., Zhang, L. & Hsieh, J. 2019. Targeting Seizure–Induced Neurogenesis in a Clinically Relevant Time Period Leads to Transient But Not Persistent Seizure Reduction. J Neurosci, 39, 7019–7028. [PMC free article: PMC6733567] [PubMed: 31308098]
- Vezzani, A., Lang, B. & Aronica, E. 2015. Immunity and Inflammation in Epilepsy. Cold Spring Harb Perspect Med, 6, a022699. [PMC free article: PMC4743070] [PubMed: 26684336]
- Victor, T. R. & Tsirka, S. E. 2020. Microglial contributions to aberrant neurogenesis and pathophysiology of epilepsy. Neuroimmunol Neuroinflamm, 7, 234–247. [PMC free article: PMC7641338] [PubMed: 33154976]
- Yang, F., Liu, Z. R., Chen, J., Zhang, S. J., Quan, Q. Y., Huang, Y. G. & Jiang, W. 2010. Roles of astrocytes and microglia in seizure–induced aberrant neurogenesis in the hippocampus of adult rats. J Neurosci Res, 88, 519–29. [PubMed: 19774666]
- Yutsudo, N., Kamada, T., Kajitani, K., Nomaru, H., Katogi, A., Ohnishi, Y. H., Ohnishi, Y. N., Takase, K., Sakumi, K., Shigeto, H. & Nakabeppu, Y. 2013. fosB–null mice display impaired adult hippocampal neurogenesis and spontaneous epilepsy with depressive behavior. Neuropsychopharmacology, 38, 895–906. [PMC free article: PMC3672000] [PubMed: 23303048]
- Zhan, R. Z. & Nadler, J. V. 2009. Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine–induced status epilepticus. J Neurophysiol, 102, 670–81. [PMC free article: PMC2724337] [PubMed: 19474175]
- Zhan, R. Z., Timofeeva, O. & Nadler, J. V. 2010. High ratio of synaptic excitation to synaptic inhibition in hilar ectopic granule cells of pilocarpine–treated rats. J Neurophysiol, 104, 3293–304. [PMC free article: PMC3007662] [PubMed: 20881195]
- Zhong, Q., Ren, B. X. & Tang, F. R. 2016. Neurogenesis in the Hippocampus of Patients with Temporal Lobe Epilepsy. Curr Neurol Neurosci Rep, 16, 20. [PubMed: 26769029]
- Zhou, Q. G., Nemes, A. D., Lee, D., Ro, E. J., Zhang, J., Nowacki, A. S., Dymecki, S. M., Najm, I. M. & Suh, H. 2019. Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits. J Clin Invest, 129, 310–323. [PMC free article: PMC6307945] [PubMed: 30507615]
- Zhu, K., Yuan, B., Hu, M., Feng, G. F., Liu, Y. & Liu, J. X. 2017. Reduced abnormal integration of adult–generated granule cells does not attenuate spontaneous recurrent seizures in mice. Epilepsy Res, 133, 58–66. [PubMed: 28431266]
- Zhu, K., Yuan, B., Hu, M., Li, C. J., Xu, J. H., Feng, G. F., Liu, Y. & Liu, J. X. 2018. Ablation of aberrant neurogenesis fails to attenuate cognitive deficit of chronically epileptic mice. Epilepsy Res, 142, 1–8. [PubMed: 29524833]
- Abstract
- Concept of Epileptogenesis
- Morphological Changes of Adult-Born Granule Cells in Epilepsy
- Molecular Regulators of Aberrant Neurogenesis in Epilepsy
- Glial Control of Aberrant Neurogenesis in Epilepsy
- Functional Roles of Adult Hippocampal Neurogenesis in Acute and Chronic Phase of Epilepsy
- Role of Aberrant Neurogenesis in Epilepsy-Associated Comorbidities
- Conclusions and Future Perspectives
- Acknowledgments
- Disclosure Statement
- References
- Roles of astrocytes and microglia in seizure-induced aberrant neurogenesis in the hippocampus of adult rats.[J Neurosci Res. 2010]Roles of astrocytes and microglia in seizure-induced aberrant neurogenesis in the hippocampus of adult rats.Yang F, Liu ZR, Chen J, Zhang SJ, Quan QY, Huang YG, Jiang W. J Neurosci Res. 2010 Feb 15; 88(3):519-29.
- Reduced abnormal integration of adult-generated granule cells does not attenuate spontaneous recurrent seizures in mice.[Epilepsy Res. 2017]Reduced abnormal integration of adult-generated granule cells does not attenuate spontaneous recurrent seizures in mice.Zhu K, Yuan B, Hu M, Feng GF, Liu Y, Liu JX. Epilepsy Res. 2017 Jul; 133:58-66. Epub 2017 Apr 11.
- Ablation of aberrant neurogenesis fails to attenuate cognitive deficit of chronically epileptic mice.[Epilepsy Res. 2018]Ablation of aberrant neurogenesis fails to attenuate cognitive deficit of chronically epileptic mice.Zhu K, Yuan B, Hu M, Li CJ, Xu JH, Feng GF, Liu Y, Liu JX. Epilepsy Res. 2018 May; 142:1-8. Epub 2018 Mar 3.
- Review Adult neurogenesis in the intact and epileptic dentate gyrus.[Prog Brain Res. 2007]Review Adult neurogenesis in the intact and epileptic dentate gyrus.Parent JM. Prog Brain Res. 2007; 163:529-40.
- Review Temporal Lobe Epileptogenesis: A Focus on Etiology, Neuron Loss, the Latent Period, and Dentate Granule Cell Disinhibition.[Jasper's Basic Mechanisms of t...]Review Temporal Lobe Epileptogenesis: A Focus on Etiology, Neuron Loss, the Latent Period, and Dentate Granule Cell Disinhibition.Sloviter RS. Jasper's Basic Mechanisms of the Epilepsies. 2024
- Adult Neurogenesis in Epileptogenesis and Comorbidities - Jasper's Basic Mechani...Adult Neurogenesis in Epileptogenesis and Comorbidities - Jasper's Basic Mechanisms of the Epilepsies
Your browsing activity is empty.
Activity recording is turned off.
See more...