José R. Pineda
Juan M. Encinas- 1Laboratory of Neural Stem Cells and Neurogenesis, Achucarro Basque Center for Neuroscience, Zamudio, Spain
- 2IKERBASQUE, The Basque Foundation for Science, Bilbao, Spain
Adult hippocampal neurogenesis is a highly plastic process that responds swiftly to neuronal activity. Adult hippocampal neurogenesis can be regulated at the level of neural stem cell recruitment and activation, progenitor proliferation, as well as newborn cell survival and differentiation. An “excitation-neurogenesis” rule was proposed after the demonstration of the capability of cultured neural stem and progenitor cells to intrinsically sense neuronal excitatory activity. In vivo, this property has remained elusive although recently the direct response of neural stem cells to GABA in the hippocampus via GABAA receptors has evidenced a mechanism for a direct talk between neurons and neural stem cells. As it is pro-neurogenic, the effect of excitatory neuronal activity has been generally considered beneficial. But what happens in situations of neuronal hyperactivity in which neurogenesis can be dramatically boosted? In animal models, electroconvulsive shock markedly increases neurogenesis. On the contrary, in epilepsy rodent models, seizures induce the generation of misplaced neurons with abnormal morphological and electrophysiological properties, namely aberrant neurogenesis. We will herein discuss what is known about the mechanisms of influence of neurons on neural stem cells, as well as the severe effects of neuronal hyperexcitation on hippocampal neurogenesis.
Introduction
Neurogenesis in the hippocampus starts with the activation of quiescent neural stem cells (NSCs), the first regulatory step that will determine the amount of new neurons generated in a given time point. Although neurogenesis is tightly linked to the level of hippocampal circuitry activity it has only been recently unveiled how gamma-aminobutyric acid (GABA) plays an essential role into translating neuronal activity into NSCs activation, as we will explain below. The question that we want to address in this review is what occurs when neuronal activity is increased to abnormal hyperexcitatory levels, especially in the clinically relevant context of epilepsy or electroconvulsive therapy (ECT) and its animal model, electroconvulsive shock (ECS). Two aspects make this question important. First, the possibility that enhanced activation of NSCs leads to a premature exhaustion of the NSC population and of neurogenesis; and second the existence of aberrant neurogenesis, i.e., the generation of neurons with ectopic location and different morphological and electrophysiological properties that can contribute to epilepsy.
NSCs, in rodents, have been shown to be able to divide symmetrically to generate more copies of themselves (Bonaguidi et al., 2011), and therefore the possibility exist that they can expand their pool. However, in normal conditions, this capability does not counteract the depletion of the NSC population that associates with age (Encinas and Enikolopov, 2008; Bonaguidi et al., 2011; Walter et al., 2011; Andersen et al., 2014). The depletion of the population is based on the activation-coupled astrocytic differentiation of NSCs. Most of the NSCs remain quiescent but once they get activated they undergo a round of several asymmetric divisions to generate neuronal precursors that either die by apoptosis and are removed by microglia, or become mature granule cells (Sierra et al., 2010). At least in mice, after finishing their round of asymmetric cell divisions NSCs differentiate into astrocytes losing their stem cell capabilities (Encinas et al., 2011). Thus, the level of activation of NSCs not only determines the level of neurogenesis but also the rate of depletion of NSCs. The prediction derived from this model is that increased activation of NSCs would lead to an initial boost of neurogenesis followed by diminished neurogenesis in the long term. This model would explain the seemingly contradictory results regarding hippocampal cell proliferation and neurogenesis in human epilepsy. Noteworthy, the dynamics of neurogenesis decline in normal conditions in humans might be different as pointed out by carbon-14-based methods (Spalding et al., 2013).
Several in vivo manipulations or brain alterations that influence electrical activity also affect adult neurogenesis. Seizures trigger an early increase of cell proliferation that involved NSCs (Huttmann et al., 2003; Indulekha et al., 2010). Also, ECS has been consistently reported (Segi-Nishida et al., 2008; Jun et al., 2015) to increase NSC recruitment and activation of NSCs. However, long-term studies addressing the fate of dividing NSCs as well as the chronic effect on the neurogenic niche are still missing. Both models of hyperexcitation are usually accompanied with the induction of neuronal death in granule cells (Zarubenko et al., 2005; Dingledine et al., 2014), which in turn might affect neurogenesis. We will focus on two aspects of neurogenesis that seem to be key regarding neuronal hyperexcitation in the hippocampus, activation and exhaustion of NSCs, and the induction of aberrant neurogenesis.
Activation and Exhaustion of NSCs
We have recently shown that in mice seizures trigger a dramatic response in the dentate gyrus (DG) leading to a swift and almost complete disruption of the neurogenic niche (Sierra et al., 2015). The main effect of seizures is to activate NSCs and induce them to differentiate into reactive astrocytes. Thus, the neurogenic potential is abandoned and the NSC pool rapidly depletes. Even though seizures trigger an initial boost of cell proliferation, mainly accounted for the activation of NSCs, in following weeks cell proliferation and neurogenesis diminish to a minimum (Sierra et al., 2015). These results could explain the chronic impairment observed in two rat models of temporal lobe epilepsy (TLE; Hattiangady et al., 2004; Hattiangady and Shetty, 2010). They also are in agreement with part of the data obtained from human samples and provide and explanation for them. Because mesial TLE (MTLE) is often resistant to drugs, surgical resection of the hippocampus as a last-resort therapeutic strategy to stop seizures is frequently performed. These samples represent a valuable source of tissue that can be analyzed without any of the drawbacks of postmortem tissue, such as degradation and overfixation.
Nestin-positive radial cells considered as putative NCSs were not found in samples from adult MTLE patients, leading the authors to suggest that the neural stem/progenitor pool might be depleted by chronic seizure activity in humans (Blümcke et al., 2001), a hypothesis that is supported in rodents by studies showing how seizure indeed recruit and activate NSCs in significantly manner (Huttmann et al., 2003) that later translates into an almost total depletion of the NSC pool (Sierra et al., 2015). Furthermore, ex vivo analysis of hippocampal neurogenesis showed that even though the epileptic human hippocampus could contain neural progenitors (Blümcke et al., 2001), these were absent in epilepsy patients with hippocampal sclerosis (Paradisi et al., 2010). The data obtained, however, are not consistent and sometimes are even contradictory when measuring other parameters. Using these samples from intractable-MTLE patients it has been shown that the immunoreactivity for PSA-NCAM (polysialic acid neural cell adhesion molecule) a specific marker of neuroblasts, or immature neurons, was lost in the neurogenic niche of the dentate gyrus (Mikkonen et al., 1998). A similar result was reported later, describing how the frequency and early onset of seizures correlated with decreased adult neurogenesis (Mathern et al., 2002). The mRNA expression of another marker of neuroblasts, doublecortin (DCX), was also decreased in MTLE patients compared to age-matched controls (Fahrner et al., 2007). The protein levels, however, did not change significantly. In contrast, an increase in the number of neural progenitors in MTLE has been suggested based on the expression of Musashi, a stem cell marker functionally related to self-renewal (Crespel et al., 2005). However, the precise cell type expressing Musashi, as well as the function of this protein in the adult hippocampus has not been explored. More conflicting evidence regarding proliferation in the MTLE hippocampus has been reported. For instance, no significant change in proliferation was found by labeling with Ki67 or minichromosome 2 (mcm2; Fahrner et al., 2007), a DNA replication licensing protein; although another study reported increased proliferation employing mcm2 (Thom et al., 2005). In general it might be inferred that an initial wave of proliferation could be followed by diminished cell division and neurogenesis, and that the age of onset, frequency and severity of the seizures will determine the neurogenic outcome in the long run. It must be considered also that human samples are obtained from individuals resistant to pharmacological treatment, which might represent only a particular subset of patients of MTLE.
Aberrant Neurogenesis
One of the most common findings in experimental models of MTLE, as well as in human samples is aberrant neurogenesis, i.e., the generation of neurons with ectopic location (located mostly into the hilus but also in the molecular layer), with abnormal ultrastructural (Dashtipour et al., 2001) and morphological features including network reorganization through mossy fiber sprouting (Parent et al., 1997), and with altered electrophysiological properties (Scharfman, 2000; Scharfman et al., 2003). One explanation for the ectopic location of neurons in MTLE could be the loss of reelin. Seizures cause death of the reelin-expressing interneurons that populate the hilus; PSA-NCAM neuroblasts express the downstream reelin signaling molecule Dab1; and in vitro, the migration of neuronal precursors is altered by manipulating the levels of reelin (Gong et al., 2007). The involvement of reelin could explain the existence of different levels of aberrant neurogenesis even when neurogenesis is greatly impaired (Murphy et al., 2012; Sierra et al., 2015). It has also been shown, that in mice lacking fibroblast growth factor (FGF) 22, ectopic location of newborn neurons is significantly reduced, suggestion that FGF22 might be playing a role in seizure-induced abnormal migration of neuroblasts (Lee and Umemori, 2013). Newly-born and developing granule cells are more sensitive to seizures than the mature and preexistent ones, and undergo noticeable changes such as the abnormal development of basal dendrites (Walter et al., 2007). The contribution of aberrant neurogenesis to MTLE is still not fully understood. A positive correlation between the number of ectopic newborn granule cells, mossy fiber sprouting, and loss of mossy cells; and the frequency of seizures was found in the intraperitoneal-pilocarpine model of mouse epilepsy (Hester and Danzer, 2013). No conclusions on causality can be extracted form that study. However, it has been recently shown that reducing neurogenesis by triggering apoptosis in dividing nestin-expressing cell reduced aberrant neurogenesis and lead to a reduction of the frequency of chronic seizures, but not of the severity or duration (Cho et al., 2015). This positive effect could not be attributed only to decreased aberrant neurogenesis, as “normal” neurogenesis was reduced as well. Importantly, the positive effect on the frequency of spontaneous seizures was abolished when the generation of reactive astrocytes following the induction of seizures was impaired.
Potential Mechanisms
GABA Signaling
Confirming previous results obtained in vitro, showing that GABAA receptors are expressed in neural progenitors in vitro (Farrant and Nusser, 2005; Ge et al., 2007), it has been more recently reported how NSCs respond directly to GABA via GABAA and GABAB receptors (Song et al., 2012; Giachino et al., 2014). GABA released by paravalbumin-expressing interneurons acts tonically on NSCs maintaining them in quiescence. Administration of the GABAA receptor agonist muscimol reduces the number of NSCs that enter the cell cycle whereas knocking down of the γ2 subunit of the GABAA receptor induces the activation of a higher number of NSCs. Interestingly, blocking the action of GABA in NSCs not only increases activation but also promotes symmetrical cell division (Song et al., 2012). In the context of MTLE, and assuming that the results found in mice regarding the massive activation and loss of NSCs (Sierra et al., 2015) could be similar in humans, treatments based on activating GABAA receptors (such as benzodiazepines) could be directly beneficial as they would preserve neurogenesis by promoting quiescence, and therefore preserving the NSC population. In a similar fashion, both the knock-out of the GABAB1 receptor and the infusion of its antagonist CGP54626A increased NSC activation, although in this case an expansion of the NSCs population, expected if symmetric division was augmented, was not found. Administration of the GABAB1 receptor baclofen decreased the number of NSCs in division (Giachino et al., 2014). Interestingly neuroblasts are a major source of GABA suggesting a retro-control or feedback mechanism for NSC quiescence as GABA exerts a tonic inhibitory control of NSC proliferation (Liu et al., 2005). In the SVZ, it was shown in vivo that treatments with the GABAAR agonist muscimol decreased cell proliferation and the number of label-retaining stem cells (LRSCs), whereas the blockade of GABAAR signaling with the specific inhibitor bicuculline increased mitosis and the number of LRSCs (Fernando et al., 2011). The authors concluded that the inhibitor bicuculline primarily increased the rate of division of already cycling stem cells. However, more recent data in which cycling cells were eradicated by using exposure to γ-radiation, showed that muscimol or bicuculline delayed and increased (respectively) the entry of quiescent NSCs into the cell cycle (Daynac et al., 2013). In the hippocampus, during the progression of the MTLE alterations of the GABAergic neuronal circuitry also take place (Maru and Ura, 2014), which in turn could affect directly NSCs. Interestingly tonic GABAergic signaling from PV can prevent their proliferation and subsequent maturation or return them to quiescence if previously activated (Moss and Toni, 2013; Song et al., 2013). Moreover, PV interneurons are capable of suppress neurogenesis during periods of high network activity and, on the other hand, facilitate neurogenesis when network activity is low (Song et al., 2012). The efficacy of GABAergic synaptic inhibition is a principal factor in controlling neuronal activity. Recent studies demonstrated that GABAA-based synaptic inhibition is decreased in the hippocampal CA1 area of patients with intractable MTLE (Maru and Ura, 2014). It remains to be elucidated what happens in local PV circuitry during seizures and if stimulation of PV in this context could be a therapeutic tool to control NSC massive activation.
Finally, another manner in which GABAergic interneurons regulate excitability is through direct action of a 36-amino acid peptide called neuropeptide Y (NPY; Colmers and El Bahh, 2003) and norepinephrine (NE; Jhaveri et al., 2015). Both are potent endogenous anticonvulsants (Erickson et al., 1996; Baraban et al., 1997; Woldbye et al., 1997; Szot et al., 1999; Weinshenker et al., 2001). Gene expression of NPY has been found to be upregulated in the hippocampus either after induction of seizures or ECS (Gruber et al., 1994; Kragh et al., 1994). It has been speculated that both transmitters, NPY and NE, likely dampen excessive excitation of neurons in brain regions implicated in epileptic seizures. However, recent findings have been demonstrated that both peptides are able to independently promote proliferation of hippocampal neural stem and progenitor cells (Decressac et al., 2011; Jhaveri et al., 2015). These findings propose that aberrant neural activity is a master key to provoke deregulation of the fine-tuning control of NSC activation and progenitor proliferation. Therefore, GABAergic input seems to be a key regulator of NSCs activation and neurogenesis, as it also has effects on other steps of the neurogenic cascade, namely survival and differentiation of neuronal progenitors (Ge et al., 2007; Song et al., 2012; Giachino et al., 2014). However, other regulatory pathways might exist and unveiling their interplay will provide the ultimate understanding of NSC activation in physiological conditions.
Other Mechanisms
Up to date it was believed that mitogenic factors participating on the induction of neurogenesis were released by dying neurons and reactive glia. In severe epilepsy such as MTLE the progression of the disease leads to a severe neuronal loss in the hippocampus (Dericioglu et al., 2013). The release of mitogenic factors can be, however, faster. After generation of seizures Shh protein from Hedgehog signaling pathway, growth factors such as FGF-2, neurotrophins such as BDNF were found to be acutely upregulated in hippocampal tissue before there was neuronal loss and then progressively diminished in chronic epilepsy (Riva et al., 1992; Lowenstein et al., 1993; Gall et al., 1994; Shetty et al., 2003, 2004; Hattiangady et al., 2004). The majority of these factors were upregulated during acute seizures, potentially reflecting an initial response to neural activity (as it happens also in ECS), independently of neuronal cell death.
BDNF Neurotrophin
Hippocampal network activity stimulates transcription of the Brain-derived neurotrophic factor (BDNF) gene and the translation of Bdnf mRNA (Mattson, 2008; Kazanis et al., 2010). BDNF is neuroprotective in a wide variety of brain pathologies (Zeev et al., 2009; Zuccato and Cattaneo, 2009). In the hippocampus BDNF is able to modulate synaptic transmission (Huang and Reichardt, 2001; Waterhouse and Xu, 2009), and in the cortex, it participates in the maturation of GABAergic inhibitory networks (Huang et al., 1999; Hong et al., 2008). Locally synthesized BDNF in dendrites of granule cells promotes differentiation and maturation of progenitor cells in the SGZ by enhancing GABA release from PV GABAergic interneurons (Waterhouse et al., 2012). Several studies have determined that seizure activity is able to increase both mRNA and protein levels (Bengzon et al., 1993). Other studies suggest that an upregulation of BDNF levels could contribute to epileptogenesis (Binder, 2004; Lähteinen et al., 2004), although at the same time it was proposed that its upregulation could be protective for neurons from excitotoxicity (Wu et al., 2004; Pérez-Navarro et al., 2005). Regarding neurogenesis, BDNF is a neurotrophin that promotes proliferation of human fetal neural stem and progenitor cells in vitro (Zhang et al., 2011) and it is a potent regulator of the survival and differentiation of adult NSCs (Park and Poo, 2013), suggesting another mechanism linking the effect of hyperexcitotoxycity on stem cell activation and neurogenesis. I has been shown that in glioma-cell populations containing cancer stem cells BDNF is able to increase directly cell division through Akt activation and PTEN inactivation (Tamura et al., 1999; Bertrand et al., 2009). Although Akt and PTEN also has been independently implicated in the proliferation of neural stem and progenitor cells (Amiri et al., 2012; Cai et al., 2014) it remains to be elucidated whether BDNF is the direct regulator.
Stimulation by FGF
Neuronal activity also can regulate growth factors such as basic FGF(bFGF) and FGF-2 (Riva et al., 1992). FGF-2 overexpression increases excitability and seizure susceptibility (Zucchini et al., 2008) and is acutely overexpressed after seizures (Indulekha et al., 2010). It is well stablished that the morphology of reactive astrocytes is controlled by FGF signaling. In a recent work Goldshmit et al. demonstrated this pleiotropic cytokine is able to decrease gliosis and increase radial glia and neural progenitor cells in spinal cord injury (Goldshmit et al., 2014). However, Kang et al. demonstrated that FGF signaling in brain is responsible for astrocyte hypertrophy in response to an inflammatory stimulus (Kang et al., 2014). Previous studies demonstrated that the expression of FGF-2 and its receptors is induced in astrocytes after epileptiform activity using KA injections in rats (Van Der Wal et al., 1994). FGF signaling is a strong mitogenic factor in vitro and in vivo when injected subcutaneously or in an intravitreal manner, stimulating cellular proliferation including astrocytes (Lewis et al., 1992; Wagner et al., 1999). In addition, in FGF-2 knock-out mice, intraperitoneal KA injection fails to trigger an increase in cell proliferation, as it does in wild-type mice (Yoshimura et al., 2001). These results support the idea that endogenously synthesized FGF-2 is necessary to stimulate adult hippocampal neurogenesis after brain insult. Interestingly, in the early phase of acute epilepsy FGF-2-expressing reactive astrocytes are observed (Erkanli et al., 2007). However, FGF-2 expression declines considerably in human chronic epilepsy (Hattiangady et al., 2004), with a decrease in parallel of the number FGF-2-positive reactive astrocytes (Erkanli et al., 2007). Reactive astrocytes persist in the chronically epileptic hippocampus, but it remains unclear whether reactive astrocytes that emerge in the early phase after SE persist for prolonged periods of time, or there is turnover and new reactive astrocytes are added progressively. The involvement of FGF signaling in the transformation of NSCs into hypertrophic reactive astrocytes (Sierra et al., 2015) has not yet been addressed.
Sonic Hedgehog Signaling
Sonic hedgehog (Shh) signal acts directly on the astrocytes and is sufficient to provoke stem cell response in both models in vitro and in vivo (Sirko et al., 2013). Shh is one of three ligands for hedegehog (Hh) signaling in mammals (Washington Smoak et al., 2005). When secreted glycoprotein Shh binds Ptc receptor on the cell surface it relieves the inhibition of Smo. Activated Smo goes to the nucleus and triggers the activation of transcription factors, which regulate proliferation, migration, and differentiation. Mice lacking Smo in NSC during development have a small DG with reduced proliferation and reduced generation of neurons (Breunig et al., 2008; Han et al., 2008).
Previous studies of ECS observed a strong and robust increase of Hh signaling through Ptc upregulation and a rapid and reduction of Smo in the hippocampal DG, proposing that both acute and chronic ECS enhanced Shh signaling in the adult hippocampus (Banerjee et al., 2005). In other experiments using the Smo antagonist cyclopamine Lai et al. observed a reduction of hippocampal neural progenitor proliferation in vivo (Lai et al., 2003). In agreement with the effects of ECS, synaptic activity involving glutamatergic transmission is proposed to regulate Smo protein, suggesting additional roles for Hh signaling in the control of hippocampal functions (Palma et al., 2005). In the KA model of epilepsy, Shh expression and release by astrocytes induces its own activation in a positive feedback loop, boosting further autocrine Shh release which translates ultimately into increased astrocytes proliferation and conversion into reactive astrocytes (Pitter et al., 2014). One study documented increased expression of Shh by neurons in the epileptic temporal lobe of human and experimental rats, although the consequences of elevated Shh were not studied (Fang et al., 2011).
Conclusions
Even though the relationship between epilepsy affecting the hippocampus and adult hippocampal neurogenesis has been known for almost two decades, many basic questions remain unsolved. One of the characteristics of the studies published so far is the apparent differential or even contradictory results among them. More than perceiving these controversial results as fruit of inconsistencies due to different animal models and the impossibility to control certain variables (especially when analyzing human tissue), we believe that they are reflecting the overwhelming biological plasticity of neurogenesis. Alterations of neurogenesis in different directions (excessive, aberrant and impaired neurogenesis) in the pathophysiology of epilepsy might be relevant to explain at least some of the cognitive symptoms associated to this disorder and we therefore conclude that further research should be carried out with an open mind in lieu of the variety of possible outcomes.
Author Contributions
All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.
Funding
This work was supported by a grant from the Spanish Ministry of Economy and Competitiveness (MINECO) with FEDER funds to JE (SAF2012-40085), and with MINECO Ramón y Cajal contracts to JE (RyC-2012-11185) and JP (RyC-2013-13450).
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Amiri, A., Cho, W., Zhou, J., Birnbaum, S. G., Sinton, C. M., McKay, R. M., et al. (2012). Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. J. Neurosci. 32, 5880–5890. doi: 10.1523/JNEUROSCI.5462-11.2012
Andersen, J., Urbán, N., Achimastou, A., Ito, A., Simic, M., Ullom, K., et al. (2014). A transcriptional mechanism integrating inputs from extracellular signals to activate hippocampal stem cells. Neuron 83, 1085–1097. doi: 10.1016/j.neuron.2014.08.004
Banerjee, S. B., Rajendran, R., Dias, B. G., Ladiwala, U., Tole, S., and Vaidya, V. A. (2005). Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis. Eur. J. Neurosci. 22, 1570–1580. doi: 10.1111/j.1460-9568.2005.04317.x
Baraban, S. C., Hollopeter, G., Erickson, J. C., Schwartzkroin, P. A., and Palmiter, R. D. (1997). Knock-out mice reveal a critical antiepileptic role for neuropeptide Y. J. Neurosci. 17, 8927–8936.
Bengzon, J., Kokaia, Z., Ernfors, P., Kokaia, M., Leanza, G., Nilsson, O. G., et al. (1993). Regulation of neurotrophin and trkA, trkB and trkC tyrosine kinase receptor messenger RNA expression in kindling. Neuroscience 53, 433–446. doi: 10.1016/0306-4522(93)90207-V
Bertrand, J., Begaud-Grimaud, G., Bessette, B., Verdier, M., Battu, S., and Jauberteau, M.-O. (2009). Cancer stem cells from human glioma cell line are resistant to Fas-induced apoptosis. Int. J. Oncol. 34, 717–727. doi: 10.3892/ijo_00000198
Binder, D. K. (2004). The role of BDNF in epilepsy and other diseases of the mature nervous system. Adv. Exp. Med. Biol. 548, 34–56. doi: 10.1007/978-1-4757-6376-8_3
Blümcke, I., Schewe, J. C., Normann, S., Brüstle, O., Schramm, J., Elger, C. E., et al. (2001). Increase of nestin-immunoreactive neural precursor cells in the dentate gyrus of pediatric patients with early-onset temporal lobe epilepsy. Hippocampus 11, 311–321. doi: 10.1002/hipo.1045
Bonaguidi, M. A., Wheeler, M. A., Shapiro, J. S., Stadel, R. P., Sun, G. J., Ming, G. L., et al. (2011). In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell 145, 1142–1155. doi: 10.1016/j.cell.2011.05.024
Breunig, J. J., Sarkisian, M. R., Arellano, J. I., Morozov, Y. M., Ayoub, A. E., Sojitra, S., et al. (2008). Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc. Natl. Acad. Sci. U.S.A. 105, 13127–13132. doi: 10.1073/pnas.0804558105
Cai, M., Zhou, Y., Zhou, B., and Lou, S. (2014). Hypoxic conditioned medium from rat cerebral cortical cells enhances the proliferation and differentiation of neural stem cells mainly through PI3-K/Akt pathways. PLoS ONE 9:e111938. doi: 10.1371/journal.pone.0111938
Cho, K.-O., Lybrand, Z. R., Ito, N., Brulet, R., Tafacory, F., Zhang, L., et al. (2015). Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline. Nat. Commun. 6, 6606. doi: 10.1038/ncomms7606
Colmers, W. F., and El Bahh, B. (2003). Neuropeptide Y and Epilepsy. Epilepsy Curr. 3, 53–58. doi: 10.1046/j.1535-7597.2003.03208.x
Crespel, A., Rigau, V., Coubes, P., Rousset, M. C., de Bock, F., Okano, H., et al. (2005). Increased number of neural progenitors in human temporal lobe epilepsy. Neurobiol. Dis. 19, 436–450. doi: 10.1016/j.nbd.2005.01.020
Dashtipour, K., Tran, P. H., Okazaki, M. M., Nadler, J. V., and 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, 261–271. doi: 10.1016/S0006-8993(00)03119-X
Daynac, M., Chicheportiche, A., Pineda, J. R., Gauthier, L. R., Boussin, F. D., and Mouthon, M.-A. (2013). Quiescent neural stem cells exit dormancy upon alteration of GABAAR signaling following radiation damage. Stem Cell Res. 11, 516–528. doi: 10.1016/j.scr.2013.02.008
Decressac, M., Wright, B., David, B., Tyers, P., Jaber, M., Barker, R. A., et al. (2011). Exogenous neuropeptide Y promotes in vivo hippocampal neurogenesis. Hippocampus 21, 233–238. doi: 10.1002/hipo.20765
Dericioglu, N., Soylemezoglu, F., Gursoy-Ozdemir, Y., Akalan, N., Saygi, S., and Dalkara, T. (2013). Cell death and survival mechanisms are concomitantly active in the hippocampus of patients with mesial temporal sclerosis. Neuroscience 237, 56–65. doi: 10.1016/j.neuroscience.2013.01.050
Dingledine, R., Varvel, N. H., and Dudek, F. E. (2014). When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv. Exp. Med. Biol. 813, 109–122. doi: 10.1007/978-94-017-8914-1_9
Encinas, J. M., and Enikolopov, G. (2008). Identifying and quantitating neural stem and progenitor cells in the adult brain. Methods Cell Biol. 85, 243–272. doi: 10.1016/S0091-679X(08)85011-X
Encinas, J. M., Michurina, T. V., Peunova, N., Park, J. H., Tordo, J., Peterson, D. A., et al. (2011). Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell 8, 566–579. doi: 10.1016/j.stem.2011.03.010
Erickson, J. C., Clegg, K. E., and Palmiter, R. D. (1996). Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415–421. doi: 10.1038/381415a0
Erkanli, G., Ercan, F., Sirvanci, S., Yananli, H. R., Onat, F., and San, T. (2007). Time-dependent changes in distribution of basic fibroblast growth factor immunoreactive cells in rat hippocampus after status epilepticus. Neurol. Res. 29, 816–823. doi: 10.1179/174313213X13789811969229
Fahrner, A., Kann, G., Flubacher, A., Heinrich, C., Freiman, T. M., Zentner, J., et al. (2007). Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp. Neurol. 203, 320–332. doi: 10.1016/j.expneurol.2006.08.023
Fang, M., Lu, Y., Chen, G.-J., Shen, L., Pan, Y.-M., and Wang, X.-F. (2011). Increased expression of sonic hedgehog in temporal lobe epileptic foci in humans and experimental rats. Neuroscience 182, 62–70. doi: 10.1016/j.neuroscience.2011.02.060
Farrant, M., and Nusser, Z. (2005). Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat. Rev. Neurosci. 6, 215–229. doi: 10.1038/nrn1625
Fernando, R. N., Eleuteri, B., Abdelhady, S., Nussenzweig, A., Andäng, M., and Ernfors, P. (2011). Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells. Proc. Natl. Acad. Sci. U.S.A. 108, 5837–5842. doi: 10.1073/pnas.1014993108
Gall, C. M., Berschauer, R., and Isackson, P. J. (1994). Seizures increase basic fibroblast growth factor mRNA in adult rat forebrain neurons and glia. Brain Res. Mol. Brain Res. 21, 190–205. doi: 10.1016/0169-328X(94)90250-X
Ge, S., Pradhan, D. A., Ming, G.-L. L., and Song, H. (2007). GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci. 30, 1–8. doi: 10.1016/j.tins.2006.11.001
Giachino, C., Barz, M., Tchorz, J. S., Tome, M., Gassmann, M., Bischofberger, J., et al. (2014). GABA suppresses neurogenesis in the adult hippocampus through GABAB receptors. Development 141, 83–90. doi: 10.1242/dev.102608
Goldshmit, Y., Frisca, F., Pinto, A. R., Pébay, A., Tang, J.-K. K. Y., Siegel, A. L., et al. (2014). Fgf2 improves functional recovery-decreasing gliosis and increasing radial glia and neural progenitor cells after spinal cord injury. Brain Behav. 4, 187–200. doi: 10.1002/brb3.172
Gong, C., Wang, T.-W., Huang, H. S., and Parent, J. M. (2007). Reelin regulates neuronal progenitor migration in intact and epileptic hippocampus. J. Neurosci. 27, 1803–1811. doi: 10.1523/JNEUROSCI.3111-06.2007
Gruber, B., Greber, S., Rupp, E., and Sperk, G. (1994). Differential NPY mRNA expression in granule cells and interneurons of the rat dentate gyrus after kainic acid injection. Hippocampus 4, 474–482. doi: 10.1002/hipo.450040409
Han, Y.-G., Spassky, N., Romaguera-Ros, M., Garcia-Verdugo, J.-M., Aguilar, A., Schneider-Maunoury, S., et al. (2008). Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat. Neurosci. 11, 277–284. doi: 10.1038/nn2059
Hattiangady, B., Rao, M. S., and Shetty, A. K. (2004). Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol. Dis. 17, 473–490. doi: 10.1016/j.nbd.2004.08.008
Hattiangady, B., and Shetty, A. K. (2010). Decreased neuronal differentiation of newly generated cells underlies reduced hippocampal neurogenesis in chronic temporal lobe epilepsy. Hippocampus 20, 97–112. doi: 10.1002/hipo.20594
Hester, M. S., and Danzer, S. C. (2013). Accumulation of abnormal adult-generated hippocampal granule cells predicts seizure frequency and severity. J. Neurosci. 33, 8926–8936. doi: 10.1523/JNEUROSCI.5161-12.2013
Hong, E. J., McCord, A. E., and Greenberg, M. E. (2008). A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron 60, 610–624. doi: 10.1016/j.neuron.2008.09.024
Huang, E. J., and Reichardt, L. F. (2001). Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736. doi: 10.1146/annurev.neuro.24.1.677
Huang, Z. J., Kirkwood, A., Pizzorusso, T., Porciatti, V., Morales, B., Bear, M. F., et al. (1999). BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755. doi: 10.1016/S0092-8674(00)81509-3
Huttmann, K., Sadgrove, M., Wallraff, A., Hinterkeuser, S., Kirchhoff, F., Steinhauser, C., et al. (2003). Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. Eur. J. Neurosci. 18, 2769–2778. doi: 10.1111/j.1460-9568.2003.03002.x
Indulekha, C. L., Sanalkumar, R., Thekkuveettil, A., and James, J. (2010). Seizure induces activation of multiple subtypes of neural progenitors and growth factors in hippocampus with neuronal maturation confined to dentate gyrus. Biochem. Biophys. Res. Commun. 393, 864–871. doi: 10.1016/j.bbrc.2010.02.101
Jhaveri, D. J., O'Keeffe, I., Robinson, G. J., Zhao, Q.-Y., Zhang, Z. H., Nink, V., et al. (2015). Purification of neural precursor cells reveals the presence of distinct, stimulus-specific subpopulations of quiescent precursors in the adult mouse hippocampus. J. Neurosci. 35, 8132–8144. doi: 10.1523/JNEUROSCI.0504-15.2015
Jun, H., Hussaini, S. M. Q., Cho, C. H., Welby, J., and Jang, M.-H. (2015). Gadd45b mediates electroconvulsive shock induced proliferation of hippocampal neural stem cells. Brain Stimul. 8, 1021–1024. doi: 10.1016/j.brs.2015.07.036
Kang, K., Lee, S.-W., Han, J. E., Choi, J. W., and Song, M.-R. (2014). The complex morphology of reactive astrocytes controlled by fibroblast growth factor signaling. Glia 62, 1328–1344. doi: 10.1002/glia.22684
Kazanis, I., Lathia, J. D., Vadakkan, T. J., Raborn, E., Wan, R., Mughal, M. R., et al. (2010). Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals. J. Neurosci. 30, 9771–9781. doi: 10.1523/JNEUROSCI.0700-10.2010
Kragh, J., Tønder, N., Finsen, B. R., Zimmer, J., and Bolwig, T. G. (1994). Repeated electroconvulsive shocks cause transient changes in rat hippocampal somatostatin and neuropeptide Y immunoreactivity and mRNA in situ hybridization signals. Exp. Brain Res. 98, 305–313. doi: 10.1007/BF00228418
Lähteinen, S., Pitkänen, A., Knuuttila, J., Törönen, P., and Castrén, E. (2004). Brain-derived neurotrophic factor signaling modifies hippocampal gene expression during epileptogenesis in transgenic mice. Eur. J. Neurosci. 19, 3245–3254. doi: 10.1111/j.0953-816X.2004.03440.x
Lai, K., Kaspar, B. K., Gage, F. H., and Schaffer, D. V. (2003). Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat. Neurosci. 6, 21–27. doi: 10.1038/nn983
Lee, C. H., and Umemori, H. (2013). Suppression of epileptogenesis-associated changes in response to seizures in FGF22-deficient mice. Front. Cell. Neurosci. 7:43. doi: 10.3389/fncel.2013.00043
Lewis, G. P., Erickson, P. A., Guérin, C. J., Anderson, D. H., and Fisher, S. K. (1992). Basic fibroblast growth factor: a potential regulator of proliferation and intermediate filament expression in the retina. J. Neurosci. 12, 3968–3978.
Liu, X., Wang, Q., Haydar, T. F., and Bordey, A. (2005). Nonsynaptic GABA signaling in postnatal subventricular zone controls proliferation of GFAP-expressing progenitors. Nat. Neurosci. 8, 1179–1187. doi: 10.1038/nn1522
Lowenstein, D. H., Seren, M. S., and Longo, F. M. (1993). Prolonged increases in neurotrophic activity associated with kainate-induced hippocampal synaptic reorganization. Neuroscience 56, 597–604. doi: 10.1016/0306-4522(93)90359-N
Maru, E., and Ura, H. (2014). [GABA(A) receptor trafficking and epilepsy]. Nihon Rinsho. 72, 790–795.
Mathern, G. W., Leiphart, J. L., De Vera, A., Adelson, P. D., Seki, T., Neder, L., et al. (2002). Seizures decrease postnatal neurogenesis and granule cell development in the human fascia dentata. Epilepsia 43(Suppl. 5), 68–73. doi: 10.1046/j.1528-1157.43.s.5.28.x
Mattson, M. P. (2008). Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann. N.Y. Acad. Sci. 1144, 97–112. doi: 10.1196/annals.1418.005
Mikkonen, M., Soininen, H., Kälviänen, R., Tapiola, T., Ylinen, A., Vapalahti, M., et al. (1998). Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex. Ann. Neurol. 44, 923–934. doi: 10.1002/ana.410440611
Moss, J., and Toni, N. (2013). A circuit-based gatekeeper for adult neural stem cell proliferation: Parvalbumin-expressing interneurons of the dentate gyrus control the activation and proliferation of quiescent adult neural stem cells. Bioessays 35, 28–33. doi: 10.1002/bies.201200136
Murphy, B. L., Hofacer, R. D., Faulkner, C. N., Loepke, A. W., and Danzer, S. C. (2012). Abnormalities of granule cell dendritic structure are a prominent feature of the intrahippocampal kainic acid model of epilepsy despite reduced postinjury neurogenesis. Epilepsia 53, 908–921. doi: 10.1111/j.1528-1167.2012.03463.x
Palma, V., Lim, D. A., Dahmane, N., Sánchez, P., Brionne, T. C., Herzberg, C. D., et al. (2005). Sonic hedgehog controls stem cell behavior in the postnatal and adult brain. Development 132, 335–344. doi: 10.1242/dev.01567
Paradisi, M., Fernández, M., Del Vecchio, G., Lizzo, G., Marucci, G., Giulioni, M., et al. (2010). Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy. Neuropathol. Appl. Neurobiol. 36, 535–550. doi: 10.1111/j.1365-2990.2010.01102.x
Parent, J. M., Yu, T. W., Leibowitz, R. T., Geschwind, D. H., Sloviter, R. S., and 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, 3727–3738.
Park, H., and Poo, M. (2013). Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci. 14, 7–23. doi: 10.1038/nrn3379
Pérez-Navarro, E., Gavaldà, N., Gratacòs, E., and Alberch, J. (2005). Brain-derived neurotrophic factor prevents changes in Bcl-2 family members and caspase-3 activation induced by excitotoxicity in the striatum. J. Neurochem. 92, 678–691. doi: 10.1111/j.1471-4159.2004.02904.x
Pitter, K. L., Tamagno, I., Feng, X., Ghosal, K., Amankulor, N., Holland, E. C., et al. (2014). The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions. Glia 62, 1595–1607. doi: 10.1002/glia.22702
Riva, M. A., Gale, K., and Mocchetti, I. (1992). Basic fibroblast growth factor mRNA increases in specific brain regions following convulsive seizures. Brain Res. Mol. Brain Res. 15, 311–318. doi: 10.1016/0169-328X(92)90123-S
Scharfman, H. E. (2000). Epileptogenesis in the parahippocampal region. Parallels with the dentate gyrus. Ann. N.Y. Acad. Sci. 911, 305–327. doi: 10.1111/j.1749-6632.2000.tb06734.x
Scharfman, H. E., Sollas, A. L., Berger, R. E., and Goodman, J. H. (2003). Electrophysiological evidence of monosynaptic excitatory transmission between granule cells after seizure-induced mossy fiber sprouting. J. Neurophysiol. 90, 2536–2547. doi: 10.1152/jn.00251.2003
Segi-Nishida, E., Warner-Schmidt, J. L., and Duman, R. S. (2008). Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc. Natl. Acad. Sci. U.S.A. 105, 11352–11357. doi: 10.1073/pnas.0710858105
Shetty, A. K., Rao, M. S., Hattiangady, B., Zaman, V., and Shetty, G. A. (2004). Hippocampal neurotrophin levels after injury: relationship to the age of the hippocampus at the time of injury. J. Neurosci. Res. 78, 520–532. doi: 10.1002/jnr.20302
Shetty, A. K., Zaman, V., and Shetty, G. A. (2003). Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: a lack of correlation between brain-derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting. J. Neurochem. 87, 147–159. doi: 10.1046/j.1471-4159.2003.01979.x
Sierra, A., Encinas, J. M., Deudero, J. J. P., Chancey, J. H., Enikolopov, G., Overstreet-Wadiche, L. S., et al. (2010). Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495. doi: 10.1016/j.stem.2010.08.014
Sierra, A., Martín-suárez, S., Valcárcel-martín, R., Pascual, J., Anderson, A. E., Baekelandt, V., et al. (2015). Neuronal hyperactivity accelerates depletion of neural stem cells and impairs hippocampal neurogenesis. Cell Stem Cell 16, 488–503. doi: 10.1016/j.stem.2015.04.003
Sirko, S., Behrendt, G., Johansson, P. A., Tripathi, P., Costa, M., Bek, S., et al. (2013). Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog glia. Cell Stem Cell 12, 426–439. doi: 10.1016/j.stem.2013.01.019
Song, J., Sun, J., Moss, J., Wen, Z., Sun, G. J., Hsu, D., et al. (2013). Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat. Neurosci. 16, 1728–1730. doi: 10.1038/nn.3572
Song, J., Zhong, C., Bonaguidi, M. A., Sun, G. J., Hsu, D., Gu, Y., et al. (2012). Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature 489, 150–154. doi: 10.1038/nature11306
Spalding, K. L., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H. B., et al. (2013). Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227. doi: 10.1016/j.cell.2013.05.002
Szot, P., Weinshenker, D., White, S. S., Robbins, C. A., Rust, N. C., Schwartzkroin, P. A., et al. (1999). Norepinephrine-deficient mice have increased susceptibility to seizure-inducing stimuli. J. Neurosci. 19, 10985–10992.
Tamura, M., Gu, J., Danen, E. H., Takino, T., Miyamoto, S., and Yamada, K. M. (1999). PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J. Biol. Chem. 274, 20693–20703. doi: 10.1074/jbc.274.29.20693
Thom, M., Martinian, L., Williams, G., Stoeber, K., and Sisodiya, S. M. (2005). Cell proliferation and granule cell dispersion in human hippocampal sclerosis. J. Neuropathol. Exp. Neurol. 64, 194–201. doi: 10.1093/jnen/64.3.194
Van Der Wal, E. A., Gomez-Pinilla, F., and Cotman, C. W. (1994). Seizure-associated induction of basic fibroblast growth factor and its receptor in the rat brain. Neuroscience 60, 311–323. doi: 10.1016/0306-4522(94)90245-3
Wagner, J. P., Black, I. B., and DiCicco-Bloom, E. (1999). Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J. Neurosci. 19, 6006–6016.
Walter, C., Murphy, B. L., Pun, R. Y. K., Spieles-Engemann, A. L., and Danzer, S. C. (2007). Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells. J. Neurosci. 27, 7541–7552. doi: 10.1523/JNEUROSCI.0431-07.2007
Walter, J., Keiner, S., Witte, O. W., and Redecker, C. (2011). Age-related effects on hippocampal precursor cell subpopulations and neurogenesis. Neurobiol. Aging 32, 1906–1914. doi: 10.1016/j.neurobiolaging.2009.11.011
Washington Smoak, I., Byrd, N. A., Abu-Issa, R., Goddeeris, M. M., Anderson, R., Morris, J., et al. (2005). Sonic hedgehog is required for cardiac outflow tract and neural crest cell development. Dev. Biol. 283, 357–372. doi: 10.1016/j.ydbio.2005.04.029
Waterhouse, E. G., An, J. J., Orefice, L. L., Baydyuk, M., Liao, G.-Y., Zheng, K., et al. (2012). BDNF promotes differentiation and maturation of adult-born neurons through GABAergic transmission. J. Neurosci. 32, 14318–14330. doi: 10.1523/JNEUROSCI.0709-12.2012
Waterhouse, E. G., and Xu, B. (2009). New insights into the role of brain-derived neurotrophic factor in synaptic plasticity. Mol. Cell. Neurosci. 42, 81–89. doi: 10.1016/j.mcn.2009.06.009
Weinshenker, D., Szot, P., Miller, N. S., Rust, N. C., Hohmann, J. G., Pyati, U., et al. (2001). Genetic comparison of seizure control by norepinephrine and neuropeptide Y. J. Neurosci. 21, 7764–7769.
Woldbye, D. P., Larsen, P. J., Mikkelsen, J. D., Klemp, K., Madsen, T. M., and Bolwig, T. G. (1997). Powerful inhibition of kainic acid seizures by neuropeptide Y via Y5-like receptors. Nat. Med. 3, 761–764. doi: 10.1038/nm0797-761
Wu, X., Zhu, D., Jiang, X., Okagaki, P., Mearow, K., Zhu, G., et al. (2004). AMPA protects cultured neurons against glutamate excitotoxicity through a phosphatidylinositol 3-kinase-dependent activation in extracellular signal-regulated kinase to upregulate BDNF gene expression. J. Neurochem. 90, 807–818. doi: 10.1111/j.1471-4159.2004.02526.x
Yoshimura, S., Takagi, Y., Harada, J., Teramoto, T., Thomas, S. S., Waeber, C., et al. (2001). FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc. Natl. Acad. Sci. U.S.A. 98, 5874–5879. doi: 10.1073/pnas.101034998
Zarubenko, I. I., Yakovlev, A. A., Stepanichev, M. Y., and Gulyaeva, N. V. (2005). Electroconvulsive shock induces neuron death in the mouse hippocampus: correlation of neurodegeneration with convulsive activity. Neurosci. Behav. Physiol. 35, 715–721. doi: 10.1007/s11055-005-0115-0
Zeev, B. B., Bebbington, A., Ho, G., Leonard, H., de Klerk, N., and Christodoulou, J. (2009). The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology 72, 1242–1247. doi: 10.1212/01.wnl.0000345664.72220.6a
Zhang, Q., Liu, G., Wu, Y., Sha, H., Zhang, P., and Jia, J. (2011). BDNF promotes EGF-induced proliferation and migration of human fetal neural stem/progenitor cells via the PI3K/Akt pathway. Molecules 16, 10146–10156. doi: 10.3390/molecules161210146
Zuccato, C., and Cattaneo, E. (2009). Brain-derived neurotrophic factor in neurodegenerative diseases. Nat. Rev. Neurol. 5, 311–322. doi: 10.1038/nrneurol.2009.54
Keywords: neurogenesis, hippocampus, neural stem cells, hyperexcitation, epilepsy
Citation: Pineda JR and Encinas JM (2016) The Contradictory Effects of Neuronal Hyperexcitation on Adult Hippocampal Neurogenesis. Front. Neurosci. 10:74. doi: 10.3389/fnins.2016.00074
Received: 15 December 2015; Accepted: 17 February 2016;
Published: 03 March 2016.
Edited by:
Alino Martinez-Marcos, Universidad de Castilla, SpainReviewed by:
Ashok K. Shetty, Texas A&M Health Science Center College of Medicine, USACarlos Vicario-Abejón, Consejo Superior de Investigaciones Científicas, Spain
Helena Mira, Instituto de Salud Carlos III, Spain
Copyright © 2016 Pineda and Encinas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Juan M. Encinas, jm.encinas@ikerbasque.org