SEARCH

SEARCH BY CITATION

Keywords:

  • Neurogenesis;
  • Status epilepticus;
  • Neuroregeneration

Summary

  1. Top of page
  2. Summary
  3. Adult Neurogenesis
  4. Adult Neurogenesis and Epilepsy
  5. Does Neurogenesis Contribute to Comorbidities of Epilepsy?
  6. Acknowledgments
  7. Disclosure
  8. References

Neurogenesis in the adult central nervous system has been well documented in several mammals including humans. By now, a plethora of data has been generated with the aim of understanding the molecular and cellular events governing neurogenesis. This growing comprehension will provide the basis for modulation of neurogenesis for therapeutic purposes, in particular in neurodegenerative diseases. Herein, we review the current knowledge on neurogenesis, in particular in the frame of epilepsy, since seizures have massive effects on neurogenesis. Conversely, some studies have suggested that aberrant neurogenesis might contribute to the development or manifestation of epilepsy and, moreover, chronic inhibition of neurogenesis in epilepsy might contribute to comorbidities of epilepsy such as cognitive deficits. Therefore, a better understanding of neurogenesis in the context of epilepsy is still required for future therapeutic purposes.


Adult Neurogenesis

  1. Top of page
  2. Summary
  3. Adult Neurogenesis
  4. Adult Neurogenesis and Epilepsy
  5. Does Neurogenesis Contribute to Comorbidities of Epilepsy?
  6. Acknowledgments
  7. Disclosure
  8. References

Although neurogenesis, that is, the generation of new neurons in the adult central nervous system has been documented in several mammalian species already in the mid-1960s (Altman & Das, 1965), the real awareness for neurogenesis in the adult brain arose upon the observation of neurogenesis in the adult, even elderly, human brain (Eriksson et al., 1998). Neurogenesis occurs predominantly in two brain regions: the subgranular zone (SGZ) of the dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles. Although SVZ-derived immature neurons migrate along the rostral migratory stream into the olfactory bulb, SGZ-derived newly born neurons stay within the DG of the hippocampal formation and functionally integrate into the preexisting neuronal network, where they acquire electrophysiologic characteristics of mature DG granule cells (van Praag et al., 2002; Carleton et al., 2003). Progress regarding adult human neurogenesis and its role in brain function is still sparse, mainly due to the lack of appropriate biomarkers and imaging tools to detect neurogenesis (for example, Ramm et al., 2009). Nevertheless, in vivo optical imaging in animal models has been developed and successfully applied to follow quantitative changes in neurogenesis (Couillard-Despres et al., 2008; Villeda et al., 2011).

Adult hippocampal neurogenesis has implications for learning and memory and vice versa (Kempermann, 2002), although the existence of animal models expressing normal learning and memory performance despite the lack of adult neurogenesis has introduced some controversy in the field (Jaholkowski et al., 2009). Moreover, the fact that neurogenesis is massively declined in aging without necessarily creating cognitive deficits underscores a putative role of adult neurogenesis in fine-tuning the brain's capacity in specific aspects of learning and memory (Couillard-Despres, 2013). For example, the addition of new neurons into a preexisting neuronal network might allow the system to adapt appropriately to new challenges. As a consequence, defects in neurogenesis might cause problems for the individual to adapt to changes in the environment and contribute to psychiatric disorders such as depression, anxiety, and schizophrenia (Sah et al., 2012).

Although a lot of knowledge on neurogenesis has been created in animal models, the functional relevance of neurogenesis in the adult human brain and the contribution to neurologic and psychiatric diseases is still of a hypothetic nature. Nevertheless, a comprehensive study correlating the learning performance in patients with epilepsy before undergoing hippocampal resections, with the level of neurogenesis in the resected hippocampi measured by immunohistologic means and with the potential of neural stem cells isolated from these hippocampi to proliferate and to differentiate into neurons strongly, suggested a role of hippocampal neurogenesis in cognition (Coras et al., 2010).

Adult Neurogenesis and Epilepsy

  1. Top of page
  2. Summary
  3. Adult Neurogenesis
  4. Adult Neurogenesis and Epilepsy
  5. Does Neurogenesis Contribute to Comorbidities of Epilepsy?
  6. Acknowledgments
  7. Disclosure
  8. References

It is well established that in animal models of temporal lobe epilepsy, acute seizures dramatically elevate the levels of SVZ as well as hippocampal neurogenesis, at least transiently over a period of 1–2 weeks (Parent et al., 1997) (for review see Andres-Mach et al., 2011). Here, neurogenesis is quantitatively enhanced at the level of progenitor proliferation as well as accelerated at the level of maturation and integration of the newly generated neurons. The initial rise in neurogenesis is followed by a long-lasting low level of neurogenesis in animal models of epilepsy (Hattiangady et al., 2004). It is important to note that reduced cell proliferation has been also observed in the hippocampus of children with frequent seizures (Mathern et al., 2002).

In addition to the quantitative changes in neurogenesis after epilepsy, major qualitative alterations have been noticed, in particular at the level of spatial integration of new neurons. Typically, newly generated neurons in the adult hippocampus migrate only a short distance into the granule cell layer, where they integrate. Surprisingly, after seizure, new neurons seem to migrate either the opposite direction into the hilus or all the way through the granular layer into the molecular layer (Parent et al., 2006). The molecular reasons for the displacement of newly generated neurons are unknown at present. Moreover, displaced neurons in the epileptic hippocampus might actually not exclusively derive from new neurons but result from a displacement of preexisting mature neurons (Fahrner et al., 2007). In addition, seizures induce mossy fiber reorganization, also in the absence of neurogenesis (Parent et al., 1999). Nevertheless, the high excitability, the synaptic input from mossy fibers and their little inhibitory input, might suggest a critical role of new neurons in the manifestation of epilepsy.

Another well-described qualitative feature of neurogenesis in epilepsy is the persistence of hilar basal dendrites. These basal dendrites are typical for immature hippocampal neurons, which in comparison to mature neurons are known to be hyperexcitable. Therefore, an attractive hypothesis might be that, in epilepsy, some of the newly generated neurons remain highly excitable for a protracted period and thus contribute to the manifestation of epilepsy (Ribak et al., 2000). Nevertheless, in summary, it is still under debate to what extent seizure-induced neurogenesis might contribute to the formation of an epileptic hippocampus.

Newly generated DG neurons, as well as their mature counterparts, extend their axon along the mossy fiber pathway into the CA3 region of the hippocampus. Although mossy fiber sprouting after epilepsy has been a well-known feature for decades, it became clear only recently that apparently only the new neurons respond to epilepsy with axonal sprouting. Moreover, such axons synapse on the displaced hilar neurons (Pierce et al., 2007). These data suggest that other mechanisms in addition to mossy fiber sprouting might contribute to enhanced hippocampal excitability during epileptogenesis.

Does Neurogenesis Contribute to Comorbidities of Epilepsy?

  1. Top of page
  2. Summary
  3. Adult Neurogenesis
  4. Adult Neurogenesis and Epilepsy
  5. Does Neurogenesis Contribute to Comorbidities of Epilepsy?
  6. Acknowledgments
  7. Disclosure
  8. References

Although intriguing, it is difficult at present to assign a causal role of seizure-induced neurogenesis to the manifestation of epilepsy. However, the reduced levels of neurogenesis in chronic epilepsy might have a strong contribution to cognitive deficits. Indeed, chronic epilepsies are strongly associated with cognitive deficits (for review, see Hermann & Seidenberg, 2007). Based on the association of neurogenesis with cognitive functions, the possibility of enhancing cognition with stimulators of neurogenesis is being heavily investigated at the moment (Couillard-Despres et al., 2011). Indeed, a recent study provided proof of principle for such a therapeutic strategy. Treatment of mice with the antidepressant fluoxetine promoted neurogenesis and learning performance in mice with chronic epilepsy (Barkas et al., 2012).

In summary, neurogenesis-associated cognitive deficits in epilepsy might arise at different levels. First, the low rate of neurogenesis in chronic epilepsy might reduce the hippocampal network's ability for learning and memory formation. Second, ectopically (hilar) displaced neurons may disturb normal network function. Therefore, a biphasic modulation of neurogenesis, that is, inhibition of seizure-induced neurogenesis during the early phase and a stimulation of neurogenesis in the chronic phase, might be an interesting therapeutic concept for the future treatment of cognitive disabilities in epilepsy (Fig. 1).

image

Figure 1. Correlations between epilepsy, neurogenesis, and cognition. Acute seizures elevate neurogenesis. At present it is still under discussion if aberrant neurogenesis contributes to the manifestations of epilepsy, but it might increase the susceptibility to seizures. Chronic seizures impair neurogenesis, which might contribute to cognitive declines associated with status epilepticus.

Download figure to PowerPoint

Acknowledgments

  1. Top of page
  2. Summary
  3. Adult Neurogenesis
  4. Adult Neurogenesis and Epilepsy
  5. Does Neurogenesis Contribute to Comorbidities of Epilepsy?
  6. Acknowledgments
  7. Disclosure
  8. References

The present work was supported by European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreements n° HEALTH-F2-2011-278850 (INMiND) and HEALTH-F2-2011-279288 (IDEA), by the state of Salzburg, and by the Propter Homines Foundation, Liechtenstein.

Disclosure

  1. Top of page
  2. Summary
  3. Adult Neurogenesis
  4. Adult Neurogenesis and Epilepsy
  5. Does Neurogenesis Contribute to Comorbidities of Epilepsy?
  6. Acknowledgments
  7. Disclosure
  8. References

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Adult Neurogenesis
  4. Adult Neurogenesis and Epilepsy
  5. Does Neurogenesis Contribute to Comorbidities of Epilepsy?
  6. Acknowledgments
  7. Disclosure
  8. References
  • Altman J, Das GD. (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319335.
  • Andres-Mach M, Fike JR, Luszczki JJ. (2011) Neurogenesis in the epileptic brain: a brief overview from temporal lobe epilepsy. Pharmacol Rep 63:13161323.
  • Barkas L, Redhead E, Taylor M, Shtaya A, Hamilton DA, Gray WP. (2012) Fluoxetine restores spatial learning but not accelerated forgetting in mesial temporal lobe epilepsy. Brain 135:23582374.
  • Carleton A, Petreanu LT, Lansford R, Alvarez-Buylla A, Lledo PM. (2003) Becoming a new neuron in the adult olfactory bulb. Nat Neurosci 6:507518.
  • Coras R, Siebzehnrubl FA, Pauli E, Huttner HB, Njunting M, Kobow K, Villmann C, Hahnen E, Neuhuber W, Weigel D, Buchfelder M, Stefan H, Beck H, Steindler DA, Blumcke I. (2010) Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain 133:33593372.
  • Couillard-Despres S. (2013) Hippocampal neurogenesis and ageing. Curr Top Behav Neurosci 15:343355.
  • Couillard-Despres S, Finkl R, Winner B, Ploetz S, Wiedermann D, Aigner R, Bogdahn U, Winkler J, Hoehn M, Aigner L. (2008) In vivo optical imaging of neurogenesis: watching new neurons in the intact brain. Mol Imaging 7:2834.
  • Couillard-Despres S, Iglseder B, Aigner L. (2011) Neurogenesis, cellular plasticity and cognition: the impact of stem cells in the adult and aging brain – a mini-review. Gerontology 57:559564.
  • Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:13131317.
  • Fahrner A, Kann G, Flubacher A, Heinrich C, Freiman TM, Zentner J, Frotscher M, Haas CA. (2007) Granule cell dispersion is not accompanied by enhanced neurogenesis in temporal lobe epilepsy patients. Exp Neurol 203:320332.
  • Hattiangady B, Rao MS, Shetty AK. (2004) Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis 17:473490.
  • Hermann B, Seidenberg M. (2007) Epilepsy and cognition. Epilepsy Curr 7:16.
  • Jaholkowski P, Kiryk A, Jedynak P, Ben Abdallah NM, Knapska E, Kowalczyk A, Piechal A, Blecharz-Klin K, Figiel I, Lioudyno V, Widy-Tyszkiewicz E, Wilczynski GM, Lipp HP, Kaczmarek L, Filipkowski RK. (2009) New hippocampal neurons are not obligatory for memory formation; cyclin D2 knockout mice with no adult brain neurogenesis show learning. Learn Mem 16:439451.
  • Kempermann G. (2002) Why new neurons? Possible functions for adult hippocampal neurogenesis. J Neurosci 22:635638.
  • Mathern GW, Leiphart JL, De Vera A, Adelson PD, Seki T, Neder L, Leite JP. (2002) Seizures decrease postnatal neurogenesis and granule cell development in the human fascia dentata. Epilepsia 43(Suppl. 5):6873.
  • Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH. (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:37273738.
  • Parent JM, Tada E, Fike JR, Lowenstein DH. (1999) Inhibition of dentate granule cell neurogenesis with brain irradiation does not prevent seizure-induced mossy fiber synaptic reorganization in the rat. J Neurosci 19:45084519.
  • Parent JM, Elliott RC, Pleasure SJ, Barbaro NM, Lowenstein DH. (2006) Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol 59:8191.
  • Pierce JP, Punsoni M, McCloskey DP, Scharfman HE. (2007) Mossy cell axon synaptic contacts on ectopic granule cells that are born following pilocarpine-induced seizures. Neurosci Lett 422:136140.
  • Ramm P, Couillard-Despres S, Plotz S, Rivera FJ, Krampert M, Lehner B, Kremer W, Bogdahn U, Kalbitzer HR, Aigner L. (2009) A nuclear magnetic resonance biomarker for neural progenitor cells: is it all neurogenesis? Stem Cells 27:420423.
  • Ribak CE, Tran PH, Spigelman I, Okazaki MM, Nadler JV. (2000) Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry. J Comp Neurol 428:240253.
  • Sah A, Schmuckermair C, Sartori SB, Gaburro S, Kandasamy M, Irschick R, Klimaschewski L, Landgraf R, Aigner L, Singewald N. (2012) Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior. Transl Psychiatry 2:e171.
  • van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. (2002) Functional neurogenesis in the adult hippocampus. Nature 415:10301034.
  • Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Despres S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:9094.