Skip to main content
SpringerLink
Log in

Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats

  • Original Article
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Ketamine has been reported to cause neonatal neurotoxicity via a neuronal apoptosis mechanism; however, no in vivo research has reported whether ketamine could affect postnatal neurogenesis in the hippocampal dentate gyrus (DG). A growing number of experiments suggest that postnatal hippocampal neurogenesis is the foundation of maintaining normal hippocampus function into adulthood. Therefore, this study investigated the effect of ketamine on hippocampal neurogenesis. Male Sprague–Dawley rats were divided into two groups: the control group (equal volume of normal saline), and the ketamine-anesthesia group (40 mg/kg ketamine in four injections at 1 h intervals). The S-phase marker 5-bromodeoxyuridine (BrdU) was administered after ketamine exposure to postnatal day 7 (PND-7) rats, and the neurogenesis in the hippocampal DG was assessed using single- or double-immunofluorescence staining. The expression of GFAP in the hippocampal DG was measured by western blot analysis. Spatial reference memory was tested by Morris water maze at 2 months after PND-7 rats exposed to ketamine treatment. The present results showed that neonatal ketamine exposure significantly inhibited neural stem cell (NSC) proliferation, decreased astrocytic differentiation, and markedly enhanced neuronal differentiation. The disruptive effect of ketamine on the proliferation and differentiation of NSCs lasted at least 1 week and disappeared by 2 weeks after ketamine exposure. Moreover, the migration of newborn neurons in the granule cell layer and the growth of astrocytes in the hippocampal DG were inhibited by ketamine on PND-37 and PND-44. Finally, ketamine caused a deficit in hippocampal-dependent spatial reference memory tasks at 2 months old. Our results suggested that ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in PND-7 rats. These findings may provide a new perspective to explain the adult neurocognitive dysfunction induced by neonatal ketamine exposure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85:523–569

    Article  CAS  PubMed  Google Scholar 

  • Altman J, Bayer SA (1990) Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods. J Comp Neurol 301:365–381

    Article  CAS  PubMed  Google Scholar 

  • Arvidsson A, Kokaia Z, Lindvall O (2001) N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci 14:10–18

    Article  CAS  PubMed  Google Scholar 

  • Asadi P, Ghafouri HB, Yasinzadeh M, Kasnavieh SM, Modirian E (2013) Ketamine and atropine for pediatric sedation: a prospective double-blind randomized controlled trial. Pediatr Emerg Care 29:136–139

    Article  PubMed  Google Scholar 

  • Ashwell KWS, Paxinos G (2008) Atlas of the developing rat nervous system. Elsevier, San Diego

    Google Scholar 

  • Barreto GE, Sun X, Xu L, Giffard RG (2011) Astrocyte proliferation following stroke in the mouse depends on distance from the infarct. PLoS ONE 6:e27881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartley J, Soltau T, Wimborne H, Kim S, Martin-Studdard A et al (2005) BrdU-positive cells in the neonatal mouse hippocampus following hypoxic-ischemic brain injury. BMC Neurosci 6:15

    Article  PubMed  PubMed Central  Google Scholar 

  • Belnoue L, Grosjean N, Ladeveze E, Abrous DN, Koehl M (2013) Prenatal stress inhibits hippocampal neurogenesis but spares olfactory bulb neurogenesis. PLoS ONE 8:e72972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Byrnes ML, Reynolds JN, Brien JF (2001) Effect of prenatal ethanol exposure during the brain growth spurt of the guinea pig. Neurotoxicol Teratol 23:355–364

    Article  CAS  PubMed  Google Scholar 

  • Dong C, Rovnaghi CR, Anand KJ (2012) Ketamine alters the neurogenesis of rat cortical neural stem progenit or cells. Crit Care Med 40:2407–2416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dupret D, Fabre A, Dobrossy MD, Panatier A, Rodriguez JJ et al (2007) Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol 5:e214

    Article  PubMed  PubMed Central  Google Scholar 

  • Dupret D, Revest JM, Koehl M, Ichas F, De Giorgi F et al (2008) Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE 3:e1959

    Article  PubMed  PubMed Central  Google Scholar 

  • Erasso DM, Camporesi EM, Mangar D, Saporta S (2013) Effects of isoflurane or propofol on postnatal hippocampal neurogenesis in young and aged rats. Brain Res 1530:1–12

    Article  CAS  PubMed  Google Scholar 

  • Esposito MS, Piatti VC, Laplagne DA, Morgenstern NA, Ferrari CC et al (2005) Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci 25:10074–10086

    Article  CAS  PubMed  Google Scholar 

  • Fang F, Xue Z, Cang J (2012) Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function. Neurosci Bull 28:499–508

    Article  CAS  PubMed  Google Scholar 

  • Guerra GG, Robertson CM, Alton GY, Joffe AR, Cave DA et al (2011) Neurodevelopmental outcome following exposure to sedative and analgesic drugs for complex cardiac surgery in infancy. Paediatr Anaesth 21:932–941

    Article  PubMed  Google Scholar 

  • Guidi S, Ciani E, Severi S, Contestabile A, Bartesaghi R (2005) Postnatal neurogenesis in the dentate gyrus of the guinea pig. Hippocampus 15:285–301

    Article  PubMed  Google Scholar 

  • Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vockler J et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74

    Article  CAS  PubMed  Google Scholar 

  • Joo JY, Kim BW, Lee JS, Park JY, Kim S et al (2007) Activation of NMDA receptors increases proliferation and differentiation of hippocampal neural progenitor cells. J Cell Sci 120:1358–1370

    Article  CAS  PubMed  Google Scholar 

  • Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355–362

    Article  CAS  PubMed  Google Scholar 

  • Keith JR, Wu Y, Epp JR, Sutherland RJ (2007) Fluoxetine and the dentate gyrus: memory, recovery of function, and electrophysiology. Behav Pharmacol 18:521–531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kempermann G, Gage FH (2002) Genetic influence on phenotypic differentiation in adult hippocampal neurogenesis. Brain Res Dev Brain Res 134:1–12

    Article  CAS  PubMed  Google Scholar 

  • Kempermann G, Gast D, Kronenberg G, Yamaguchi M, Gage FH (2003) Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 130:391–399

    Article  CAS  PubMed  Google Scholar 

  • Kitayama T, Yoneyama M, Tamaki K, Yoneda Y (2004) Regulation of neuronal differentiation by N-methyl-D-aspartate receptors expressed in neural progenitor cells isolated from adult mouse hippocampus. J Neurosci Res 76:599–612

    Article  CAS  PubMed  Google Scholar 

  • Liu F, Paule MG, Ali S, Wang C (2011) Ketamine-induced neurotoxicity and changes in gene expression in the developing rat brain. Curr Neuropharmacol 9:256–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193

    Article  CAS  PubMed  Google Scholar 

  • Luk KC, Kennedy TE, Sadikot AF (2003) Glutamate promotes proliferation of striatal neuronal progenitors by an NMDA receptor-mediated mechanism. J Neurosci 23:2239–2250

    CAS  PubMed  Google Scholar 

  • Luskin MB (1993) Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11:173–189

    Article  CAS  PubMed  Google Scholar 

  • Manning EE, Ransome MI, Burrows EL, Hannan AJ (2012) Increased adult hippocampal neurogenesis and abnormal migration of adult-born granule neurons is associated with hippocampal-specific cognitive deficits in phospholipase C-beta1 knockout mice. Hippocampus 22:309–319

    Article  PubMed  Google Scholar 

  • Mongiat LA, Schinder AF (2011) Adult neurogenesis and the plasticity of the dentate gyrus network. Eur J Neurosci 33:1055–1061

    Article  PubMed  Google Scholar 

  • Nacher J, McEwen BS (2006) The role of N-methyl-D-asparate receptors in neurogenesis. Hippocampus 16:267–270

    Article  CAS  PubMed  Google Scholar 

  • Nacher J, Rosell DR, Alonso-Llosa G, McEwen BS (2001) NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci 13:512–520

    Article  CAS  PubMed  Google Scholar 

  • Nie H, Peng Z, Lao N, Dong H, Xiong L (2013) Effects of sevoflurane on self-renewal capacity and differentiation of cultured neural stem cells. Neurochem Res 38:1758–1767

    Article  CAS  PubMed  Google Scholar 

  • Paule MG, Li M, Allen RR, Liu F, Zou X et al (2011) Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 33:220–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, vol 2. Academic Press, Sydney

    Google Scholar 

  • Pfenninger EG, Durieux ME, Himmelseher S (2002) Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers. Anesthesiology 96:357–366

    Article  CAS  PubMed  Google Scholar 

  • Porzionato A, Macchi V, Zaramella P, Sarasin G, Grisafi D et al (2013) Effects of postnatal hyperoxia exposure on the rat dentate gyrus and subventricular zone. Brain Struct Funct 220(1):229–247

    Article  PubMed  Google Scholar 

  • Sibbe M, Forster E, Basak O, Taylor V, Frotscher M (2009) Reelin and Notch1 cooperate in the development of the dentate gyrus. J Neurosci 29:8578–8585

    Article  CAS  PubMed  Google Scholar 

  • Stone SS, Teixeira CM, Zaslavsky K, Wheeler AL, Martinez-Canabal A et al (2011) Functional convergence of developmentally and adult-generated granule cells in dentate gyrus circuits supporting hippocampus-dependent memory. Hippocampus 21:1348–1362

    Article  PubMed  Google Scholar 

  • Stratmann G, May LD, Sall JW, Alvi RS, Bell JS et al (2009a) Effect of hypercarbia and isoflurane on brain cell death and neurocognitive dysfunction in 7-day-old rats. Anesthesiology 110:849–861

    Article  CAS  PubMed  Google Scholar 

  • Stratmann G, Sall JW, May LD, Bell JS, Magnusson KR et al (2009b) Isoflurane differentially affects neurogenesis and long-term neurocognitive function in 60-day-old and 7-day-old rats. Anesthesiology 110:834–848

    Article  CAS  PubMed  Google Scholar 

  • Vadodaria KC, Jessberger S (2014) Functional neurogenesis in the adult hippocampus: then and now. Front Neurosci 8:55

    Article  PubMed  PubMed Central  Google Scholar 

  • van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD et al (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034

    Article  PubMed  Google Scholar 

  • Wilder RT, Flick RP, Sprung J, Katusic SK, Barbaresi WJ, Mickelson C, Gleich SJ, Schroeder DR, Weaver AL, Warner DO (2009) Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 110:796–804

    Article  PubMed  PubMed Central  Google Scholar 

  • Young D, Lawlor PA, Leone P, Dragunow M, During MJ (1999) Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 5:448–453

    Article  CAS  PubMed  Google Scholar 

  • Yu-Qing Wu, Liang Tuo, Huang He et al (2014) Ketamine inhibits proliferation of neural stem cell from neonatal rat hippocampus in vitro. Cell Physiol Biochem 34:1792–1801

    Article  Google Scholar 

  • Zhang K, Zhao T, Huang X, Wu LY, Wu K et al (2014) Notch1 mediates postnatal neurogenesis in hippocampus enhanced by intermittent hypoxia. Neurobiol Dis 64:66–78

    Article  CAS  PubMed  Google Scholar 

  • Zou X, Patterson TA, Divine RL, Sadovova N, Zhang X et al (2009a) Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain. Int J Dev Neurosci 27:727–731

    Article  CAS  PubMed  Google Scholar 

  • Zou X, Patterson TA, Sadovova N, Twaddle NC, Doerge DR et al (2009b) Potential neurotoxicity of ketamine in the developing rat brain. Toxicol Sci 108:149–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81171013), the Key Subject of Colleges and Universities Natural Science Foundation of Jiangsu Province (10KJA320052).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    He Huang, Cun-Ming Liu & Jie Sun

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China

    Ting Hao, Chun-Mei Xu, Dan Wang & Yu-Qing Wu

Authors
  1. He Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cun-Ming Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jie Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ting Hao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chun-Mei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-Qing Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Qing Wu.

Ethics declarations

Conflict of interest

The authors have declared that no competing interests exist.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, H., Liu, CM., Sun, J. et al. Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats. Neurotox Res 30, 185–198 (2016). https://doi.org/10.1007/s12640-016-9615-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-016-9615-7

Keywords

Search

Navigation