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. Author manuscript; available in PMC: 2009 Jun 23.
Published in final edited form as: Epilepsia. 2008 Jun;49(Suppl 5):50–54. doi: 10.1111/j.1528-1167.2008.01637.x

Neurogenesis and Epilepsy in the Developing Brain

Brenda E Porter
PMCID: PMC2700768  NIHMSID: NIHMS116002  PMID: 18522600

Summary

Multiple studies have highlighted how seizures induce different molecular, cellular and physiologic consequences in an immature as compared to a mature brain. In keeping with these studies, seizures early in life alter dentate granule cell birth in different and even opposing fashion to adult seizure models (see Table1). During the first week of rodent post-natal life, seizures decrease cell birth in the post-ictal period but do not alter maturation of newborn cells. Seizures during the second week of life have varied effects on dentate granule cell birth, either causing no change or increasing birth, and may promote a mild increase in neuronal survival. During the third and fourth weeks of life, seizures begin to increase cell birth similar to that seen in adult seizure models. Interestingly, animals that experienced seizure during the first month of life have an increase in cell birth during adulthood opposite to the reported decrease in chronic animals experiencing a prolonged seizure as an adult. Children have more ongoing cell birth in the dentate gyrus than adults and markers of cell division are further increased in children with refractory temporal lobe epilepsy. There are clear age dependent differences in how seizures alter cell birth in the dentate gyrus both acutely and chronically. Future studies need to focus on how these changes in neurogenesis influence dentate gyrus function, and what they imply for epileptogenesis and the learning and memory impairments so commonly found in children with temporal lobe epilepsy.

The robust alteration in neurogenesis following an episode of status epilepticus is an interesting phenomenon and begs the question of how this change might contribute to epilepsy as well at temporal lobe dysfunction. In early life seizure animal models and children that experience early life seizures, there is a lower seizure threshold, increased risk for developing epilepsy and cognitive dysfunction later in life. Here we begin to address how changes in regulation of cell birth in the dentate gyrus following seizures during development might contribute to these problems. We start by describing how seizures alter dentate gyrus neurogenesis during rodent development and then turn to what is known about neurogenesis in children with epilepsy.

The majority of cortical neurogenesis occurs early during prenatal development: 16 weeks gestation in humans and by 15 days post fertilization in rodents. The hippocampus and cerebellum, however, are late-developing neuronal structures, completing formation after 34 weeks gestation in humans and during the first 2 weeks of post-natal life in the rat (Bayer 1980; Arnold and Trojanowski 1996; Hauser, Khurdayan et al. 2003). Therefore, if seizures have an effect on brain development it is most likely to be in these late developing neuronal structures. Hence, in premature infants and immature rodent epilepsy models, seizures early in life might influence neurogenesis that is required for the formation of the hippocampus and cerebellum. Here we discuss the effects of seizures early in life on cell birth in the dentate gyrus both at acute and chronic time points, and what is known about how the seizures alter maturation of the newborn cells.

Post-natal week 1 in rat

Work in the 1970’s by Wasterlain and colleagues suggested that seizures within the first week of life decrease the rate of cell birth in the brain, though they did not identify the primary cell type affected (Wasterlain and Plum 1973; Wasterlain 1975). More recently, focusing on the effect of multiple brief seizures during the first post-natal week, the laboratory of Dr. Greg Holmes showed that seizures both promote and suppress cell birth in the dentate gyrus depending on when cell birth is measured in relationship to the seizure (Holmes, Gairsa et al. 1998; McCabe, Silveira et al. 2001). The timing of the thymidine analog injection, bromo-deoxyuridine (BrdU), determined whether the seizure appeared to increase or decrease cell birth in the dentate gyrus. If BrdU was given just prior to a brief flurothyl-induced seizure there was a small increase in BrdU labeling suggesting that, during the seizure, BrdU incorporation and cell birth in the dentate gyrus is increased. In contrast, if the BrdU was injected following multiple flurothyl induced seizures there was a decrease in BrdU labeling. Thus, cell birth is suppressed in the post-ictal period following multiple brief seizures during the first week of life. They confirmed that the post-ictal decrease was age related and found an increase in dentate granule cell birth following multiple flurothyl seizures in mature animals. In immature animals the decrease in BrdU labeling persisted for 2 weeks and the majority of labeled cells in both the control and flurothyl-treated rats eventually expressed mature neuronal markers. Suggesting the seizure did not alter differentiation of the newborn cells. Consistent with the findings of the Holmes laboratory, Yu and colleagues used repetitive doses of pilocarpine to induce seizures during the first week of life and found an approximately forty percent reduction in BrdU labeling for the weeks following seizure induction (Xiu-Yu, Ruo-Peng et al. 2007). Liu and colleagues injected kainate at several ages from P6 to P13 to cause multiple seizures and found a decrease in cell birth in the post-ictal period (Liu, Kaur et al. 2003). Taken together, seizures during the first week of life, in contrast to seizures in adults, repress cell birth during the post-ictal period in the dentate gyrus with suppression persisting for several weeks after the seizure.

The mechanism for post-ictal suppression of neurogenesis following seizures in the first week of life is not understood. One possible explanation is that seizures interact differently with the initial wave of neurogenesis important for the formation of the dentate gyrus, versus the ongoing replacement of neurons found at later ages. Alternatively, seizures early in life produce distinct physiologic and molecular changes that are age specific and might be responsible for the unique decrease in cell birth during the first week of life.

Interestingly, decreased cell birth in the dentate gyrus lasts for two weeks after the pilocarpine-induced seizures and is then followed by an increase in cell birth at chronic time points. These data contrast with decreased neurogenesis at chronic time points in adult seizure models (Hattiangady, Rao et al. 2004; Kralic, Ledergerber et al. 2005). Further studies are needed to determine if the chronic increase in cell birth following first week of life seizures is found in other seizure models such as flurothyl. These findings imply that seizures during the first week of life have very different short and long-term influences on cell birth and neurogenesis compared to older age groups.

Rat post-natal week 2

During the second week of life the chemoconvuslants, kainic acid and lithium-pilocarpine, and the hyperthermia model of febrile seizures have been used to induce seizures and measure cell birth in the dentate gyrus. The findings across models are not consistent, for example kainate and pilocarpine seizures increase neurogenesis during the post-ictal period (Sankar, Shin et al. 2000; Bender, Dube et al. 2003). Conversely, in the P10 hypertherthermia seizure model there was no immediate post-ictal change in cell birth in the week following the seizure (Bender, Dube et al. 2003; Lemmens, Lubbers et al. 2005). However, if the hyperthermia treated animals were labeled with BrdU during the week following the seizure and sacrificed in adulthood there was a modest increase in labeled cells in the female but not the male littermates (Lemmens, Lubbers et al. 2005). This suggests a mild increase in long-term dentate granule neuron survival following P10 hyperthermia seizures in female rats. It is not known if there are differences in long-term survival and/or maturation of newborn cells following kainate and pilocarpine induced seizures at this age.

The method of seizure induction appears to be important in determining if and how seizures influence cell birth. Why there is a strong difference in how each method influences cell birth in the dentate gyrus is not understood, but may relate to the mechanism of seizure induction. The difference in neurogenesis between P10 kainate, pilocarpine and hyperthermia induced seizures allows for speculation about the role neurogenesis plays in epileptogenesis. Animals that experienced lithium pilocarpine provoked seizures at P10 do not develop spontaneous seizures, though they do have lowered seizure thresholds for subsequent chemoconvulsant challenges (Dube, Boyet et al. 2001; Zhang, Raol et al. 2004; Zhang, Raol et al. 2004). In contrast, hyperthermia seizures at P10 cause a subset of animals, approximately one third, to develop brief spontaneous seizures in adulthood (Dube, Richichi et al. 2006). The lack of altered neurogenesis following hyperthermia-induced seizures suggests that altered cell birth does not contribute to epileptogenesis in these animals. Further studies are needed to determine if the increase in neurogenesis in the pilocarpine and kainate models at this age contribute to a lowered seizure threshold or learning and memory differences in adulthood (Holmes 2005).

Rat post-natal week 3-4

At what age do seizures in rodents induce changes in cell birth and differentiation that is similar to adults? Kainate induced seizures at one month and three months of age induces similar increases in cell birth (Gray, May et al. 2002). During the third post-natal week pilocarpine chemoconvulsants appear to induce an increase in cell birth that may be slightly more robust than P10 and closer to the adult, however dosing and methodological differences make it difficult to be certain. There is a several-fold increase in cell birth following lithium pilocarpine induced seizures at P20 (Sankar, Shin et al. 2000; Porter, Maronski et al. 2004). Akman and colleagues found an immediate decrease in neurogenesis following lithium-pilocarpine seizures at P20. The difference may be model specific as Akman used diazepam to stop the seizure at two hours and γ-aminobutyric acid (GABA) agonists have been reported to decrease neurogenesis (Akman, Zhao et al. 2004; Tozuka, Fukuda et al. 2005). Use of GABA agonists in the adult pilocarpine model may explain the more immediate increase in cell birth in the P10 and P20 lithium pilocarpine model which do not use benzodiazepines or barbiturates to stop the status epilepticus (Parent, Yu et al. 1997; Sankar, Shin et al. 2000).

In addition to the increased cell birth following lithium pilocarpine induced status epilepticus at P20, there is also an increase in dying immature and mature dentate granule neurons resulting in approximately three -fold more immature dentate granule neurons in the weeks following the seizure (Porter, Maronski et al. 2004). How seizures increase the birth of dentate gyrus cells following a seizure is not well understood and requires further study. For instance, it is not known if dentate granule birth and death are synchronized. A feedback mechanism seems likely, as the size of the dentate gyrus does not dramatically change throughout life.

The immature neurons born following the P20 pilocarpine induced seizure express a variety of neurotransmitters receptors, including AMPA and kainite receptors that are relatively unaffected by prolonged seizures (Porter, Cui et al. 2006). In contrast the mature neurons likely present during the episode of status epilepticus undergo a variety of changes in their AMPA and kainate receptor expression. One hypothesis from these data is that the immature cells offer a pool of cells with a seizure naïve phenotype for potential manipulation to suppress epileptogenesis or improve learning and memory.

Following lithium pilocarpine induced status epilepticus at postnatal day 20 approximately fifty percent of the animals go on to develop spontaneous seizures (Dube, Boyet et al. 2001; Dube, da Silva Fernandes et al. 2001; Raol, Budreck et al. 2003). The adult animals that eventually develop spontaneous seizures have a approximately two-fold increase in cell birth in the dentate gyrus as compared to those without spontaneous seizures or control animals (Cha, Akman et al. 2004). The chronic spontaneous seizure animals did not experience seizures in the period immediately preceding the BrdU injections but it was not certain if they remained seizure free for the duration of the experiment following the BrdU injections. This chronic increase in cell birth in animals developing spontaneous seizures following status epilepticus at P20 is opposite to the decrease in cell birth in chronic adult epilepsy models (Hattiangady, Rao et al. 2004; Kralic, Ledergerber et al. 2005). Memory impairment has been found in adult animals following lithium pilocarpine status epilepticus at P20, but it is not known if the increase in cell birth is related to the poor memory performance (Liu, Gatt et al. 1994).

Changes in cell birth and neurogenesis in children with epilepsy

A number of studies have tried to assess cell birth and neurogenesis in epilepsy surgery specimens from children with medically refractory epilepsy and tumor related epilepsy. Because BrdU cannot be used as a marker of cell division in human surgical and post-mortem tissue, researchers have had to use biomarkers of stem cell number and division such as the proteins nestin and Ki-67, and immature dentate granule neuron marker PSA-NCAM. Because nestin, Ki-67 and PSA-NCAM are only biomarkers, age or seizures might alter antigen expression without an actual change in stem cell number, cell division or immature neurons. In autopsy control specimens and epilepsy surgical specimens, stem and dividing cell numbers appear to be greatest early in life and fall with age (Blumcke, Schewe et al. 2001; Fahrner, Kann et al. 2007). Epilepsy with evidence of hippocampal pathology such as Ammon’s horn sclerosis in infants and young children is associated with increased numbers of stem and dividing cells compared with age matched controls (Blumcke, Schewe et al. 2001; Takei, Wilfong et al. 2007). The increase in stem and dividing cells in pediatric patients with epilepsy and hippocampal pathology is similar to most (Crespel, Rigau et al. 2005; Thom, Zhou et al. 2005) but not all (Fahrner, Kann et al. 2007) adult epilepsy histopathologic case series. In contrast to the increase in markers of stem cell and cell division in children with epilepsy, there was a decrease in PSA-NCAM staining intensity, a marker of immature dentate granule neurons in pediatric epilepsy surgical specimens (Mathern, Leiphart et al. 2002). If confirmed with other markers of immature dentate granule neurons, such as doublecortin, the presence of increased total and dividing stem cells in the dentate gyrus of pediatric temporal lobe epilepsy patients suggests a loss or diversion of cells on the path to dentate granule neuronal maturation.

Summary

Seizures at all stages of development alter cell birth and neurogenesis in the rodent dentate gyrus (see Table 1). The age at the time of the seizure dramatically alters how the seizure influences cell birth and neurogenesis both acutely and chronically. Multiple seizures types during post-natal week one of life cause a prolonged post-ictal decrease in cell birth and neurogenesis. During the second postnatal week of life some seizure types do not alter cell birth while others cause a post-ictal increase. Seizures during the third and fourth week of life cause an increase in cell birth and neurogenesis. Animals exposed to a variety of seizure types during the first month of life have a mild increase in cell birth when evaluated in adulthood. A better understanding of these age dependent differences in seizure induced alteration in neurogenesis will help with determining the role of neurogenesis in epileptogenesis and learning and memory impairments in epilepsy.

Table 1.

Age Seizure Model Acute & Subacute Changes in Cell Birth Chronic Changes in Cell Birth
<1 Flurothyl Increased Ictal1 & Decreased Post-Ictal2 ND
1st Week of Life Pilocarpine Decreased Post-Ictal3 Increased3
Kainate Decreased4 ND
2nd Week of Life Pilocarpine Increased5 ND
Kainate Increased6 ND
Hyperthermia No change6,7 Slight increase in new cell survival (female only)7
3rd-4th Week of Life Pilocarpine Increased5,8 Increased in those animals that develop spontaneous seizures.10
Kainate Increased9 (similar to adults) ND
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ND-Not Determined

1

Holmes et al. 2008

Future Research

Over the past few years, neuroscientists have made progress on describing the phenomenon of seizure-induced alterations in dentate gyrus neurogenesis during development. In the future researchers will need to go beyond these descriptive studies and begin to determine if changes in neurogenesis are important for epileptogenesis and temporal lobe dysfunction. The mechanism by which seizures alter neurogenesis will need to be determined, as well as the large age-dependent and model-specific differences in how seizures influence neurogenesis. Understanding the mechanism by which seizures alter neurogenesis will have far reaching effects not only for epilepsy but also in the fields of depression and memory impairment.

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