Advertisement

Neurotoxicity Research

, Volume 17, Issue 2, pp 179–188 | Cite as

General Anesthesia Causes Long-Lasting Disturbances in the Ultrastructural Properties of Developing Synapses in Young Rats

  • N. LunardiEmail author
  • C. Ori
  • A. Erisir
  • V. Jevtovic-Todorovic
Article

Abstract

Common general anesthetics administered to young rats at the peak of brain development cause widespread apoptotic neurodegeneration in their immature brain. Behavioral studies have shown that this leads to learning and memory deficiencies later in life. The subiculum, a part of the hippocampus proper and Papez’s circuit, is involved in cognitive development and is vulnerable to anesthesia-induced developmental neurodegeneration. This degeneration is manifested by acute substantial neuroapoptotic damage and permanent neuronal loss in later stages of synaptogenesis. Since synapse formation is a critical component of brain development, we examined the effects of highly neurotoxic anesthesia combination (isoflurane, nitrous oxide, and midazolam) on ultrastructural development of synapses in the rat subiculum. We found that this anesthesia, when administered at the peak of synaptogenesis, causes long-lasting injury to the subicular neuropil. This is manifested as neuropil scarcity and disarray, morphological changes indicative of mitochondria degeneration, a decrease in the number of neuronal profiles with multiple synaptic boutons and significant decreases in synapse volumetric densities. We believe that observed morphological disturbances of developing synapses may, at least in part, contribute to the learning and memory deficits that occur later in life after exposure of the immature brain to general anesthesia.

Keywords

Isoflurane Nitrous oxide Midazolam Synaptogenesis Subiculum Neurotoxicity 

Notes

Acknowledgments

This study was supported by the NIH/NICHD HD 44517 (to V.J-T.) and Harold Carron endowment (to V.J-T). V.J-T. is an Established Investigator of the American Heart Association. The authors thank Jan Redick, Lisa Carter, and the Advanced Microscopy Facility at the University of Virginia Health System for technical assistance with electron microscopy.

References

  1. Ahmed MG, Bedi KS, Warren MA, Kamel MM (1987) Effects of a lengthy period of undernutrition from birth and subsequent nutritional rehabilitation on the synapse: granule cell neuron ratio in the rat dentate gyrus. J Comp Neurol 263:146–158CrossRefPubMedGoogle Scholar
  2. Bittigau P, Sifringer M, Pohl D, Stadthaus D, Ishimaru M, Shimizu H, Ikeda M, Lang D, Speer A, Olney JW, Ikonomidou C (1999) Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann Neurol 45:724–735CrossRefPubMedGoogle Scholar
  3. Briones TL, Suh E, Jozsa L, Hattar H, Chai J, Wadowska M (2004) Behaviorally-induced ultrastructural plasticity in the hippocampal region after cerebral ischemia. Brain Res 997:137–146CrossRefPubMedGoogle Scholar
  4. Chang LW, Dudley AW Jr, Lee YK, Katz J (1974) Ultrastructural changes in the nervous system after chronic exposure to halothane. Exp Neurol 45:209–219CrossRefPubMedGoogle Scholar
  5. Chang LW, Dudley AW Jr, Katz J (1976) Pathological changes in the nervous system following in utero exposure to halothane. Environ Res 11:40–51CrossRefPubMedGoogle Scholar
  6. Chua EF, Schacter DL, Rand-Giovannetti E, Sperling RA (2006) Understanding metamemory: neural correlates of the cognitive process and subjective level of confidence in recognition memory. Neuroimage 29:1150–1160CrossRefPubMedGoogle Scholar
  7. Crain B, Cotman C, Taylor D, Lynch G (1973) A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat. Brain Res 63:195–204CrossRefPubMedGoogle Scholar
  8. Day M, Wang Z, Ding J, An X, Ingham CA, Shering AF, Wokosin D, Ilijic E, Sun Z, Sampson AR, Mugnaini E, Deutch AY, Sesack SR, Arbuthnott GW, Surmeier DJ (2006) Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models. Nat Neurosci 9:251–259CrossRefPubMedGoogle Scholar
  9. Devi L, Diwakar L, Raju TR, Kutty BM (2003) Selective neurodegeneration of hippocampus and entorhinal cortex correlates with spatial learning impairments in rats with bilateral ibotenate lesions of ventral subiculum. Brain Res 960:9–15CrossRefPubMedGoogle Scholar
  10. Dudanova I, Tabuchi K, Rohlmann A, Sudhof TC, Missler M (2007) Deletion of alpha-neurexins does not cause a major impairment of axonal pathfinding or synapse formation. J Comp Neurol 502:261–274CrossRefPubMedGoogle Scholar
  11. Erisir A, Harris JL (2003) Decline of the critical period of visual plasticity is concurrent with the reduction of NR2B subunit of the synaptic NMDA receptor in layer 4. J Neurosci 23:5208–5218PubMedGoogle Scholar
  12. Franks NP (2008) General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 9:370–386CrossRefPubMedGoogle Scholar
  13. Galani R, Weiss I, Cassel JC, Kelche C (1998) Spatial memory, habituation, and reactions to spatial and nonspatial changes in rats with selective lesions of the hippocampus, the entorhinal cortex or the subiculum. Behav Brain Res 96:1–12CrossRefPubMedGoogle Scholar
  14. Garcia JH, Lassen NA, Weiller C, Sperling B, Nakagawara J (1996) Ischemic stroke and incomplete infarction. Stroke 27:761–765PubMedGoogle Scholar
  15. Giffard C, Landeau B, Kerrouche N, Young AR, Barré L, Baron JC (2008) Decreased chronic-stage cortical 11C-flumazenil binding after focal ischemia-reperfusion in baboons: a marker of selective neuronal loss? Stroke 39:991–999CrossRefPubMedGoogle Scholar
  16. Granados-Rojas L, Aguilar A, Díaz-Cintra S (2004) The mossy fiber system of the hippocampal formation is decreased by chronic and postnatal but not by prenatal protein malnutrition in rats. Nutr Neurosci 7:301–308CrossRefPubMedGoogle Scholar
  17. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vöckler J, Dikranian K, Tenkova TI, Stefovska V, Turski L, Olney JW (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74CrossRefPubMedGoogle Scholar
  18. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price MT, Stefovska V, Hörster F, Tenkova T, Dikranian K, Olney JW (2000) Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 287:1056–1060CrossRefPubMedGoogle Scholar
  19. Inquimbert P, Rodeau JL, Schlichter R (2008) Regional differences in the decay kinetics of GABA(A) receptor-mediated miniature IPSCs in the dorsal horn of the rat spinal cord are determined by mitochondrial transport of cholesterol. J Neurosci 28:3427–3437CrossRefPubMedGoogle Scholar
  20. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, Powell S, Dikranian K, Benshoff N, Zorumski CF, Olney JW (1998) Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med 4:460–463CrossRefPubMedGoogle Scholar
  21. Jevtovic-Todorovic V, Benshoff N, Olney JW (2000) Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats. Br J Pharmacol 130:1692–1698CrossRefPubMedGoogle Scholar
  22. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci 23:876–882PubMedGoogle Scholar
  23. Jonas E (2004) Regulation of synaptic transmission by mitochondrial ion channels. J Bioenerg Biomembr 36:357–361CrossRefPubMedGoogle Scholar
  24. Kovalenko T, Osadchenko I, Nikonenko A, Lushnikova I, Voronin K, Nikonenko I, Muller D, Skibo G (2006) Ischemia-induced modifications in hippocampal CA1 stratum radiatum excitatory synapses. Hippocampus 16:814–825CrossRefPubMedGoogle Scholar
  25. Kurt MA, Kafa MI, Dierssen M, Davies DC (2004) Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome. Brain Res 1022:101–109CrossRefPubMedGoogle Scholar
  26. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24:10191–10200CrossRefPubMedGoogle Scholar
  27. Laxmi TR, Bindu PN, Raju TR, Meti BL (1999) Spatial memory impairment in ventral subicular lesioned rats. Brain Res 816:245–248CrossRefPubMedGoogle Scholar
  28. Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887CrossRefPubMedGoogle Scholar
  29. Lister JP, Blatt GJ, DeBassio WA, Kemper TL, Tonkiss J, Galler JR, Rosene DL (2005) Effect of prenatal protein malnutrition on numbers of neurons in the principal cell layers of the adult rat hippocampal formation. Hippocampus 15:393–403CrossRefPubMedGoogle Scholar
  30. Lodge D, Anis NA (1982) Effects of phencyclidine on excitatory amino acid activation of spinal interneurones in the cat. Eur J Pharmacol 77:203–204CrossRefPubMedGoogle Scholar
  31. Loepke AW, Istaphanous GK, McAuliffe JJIII, Miles L, Hughes EA, McCann JC, Harlow KE, Kurth CD, Williams MT, Vorhees CV, Danzer SC (2009) The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory. Anesth Analg 108:90–104CrossRefPubMedGoogle Scholar
  32. Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V (2006) General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 11:1603–1615CrossRefPubMedGoogle Scholar
  33. McNaughton N (2006) The role of the subiculum within the behavioural inhibition system. Behav Brain Res 174:232–250CrossRefPubMedGoogle Scholar
  34. Mennerick S, Jevtovic-Todorovic V, Todorovic SM, Shen W, Olney JW, Zorumski CF (1998) Effect of nitrous oxide on excitatory and inhibitory synaptic transmission in hippocampal cultures. J Neurosci 18:9716–9726PubMedGoogle Scholar
  35. Mody I (2005) Aspects of the homeostatic plasticity of GABAA receptor-mediated inhibition. J Physiol. 562:37–46CrossRefPubMedGoogle Scholar
  36. Morris RG, Schenk F, Tweedie F, Jarrard LE (1990) Ibotenate lesions of hippocampus and/or subiculum: dissociating components of allocentric spatial learning. Eur J Neurosci 2:1016–1028CrossRefPubMedGoogle Scholar
  37. Munno DW, Syed NI (2003) Synaptogenesis in the CNS: an odyssey from wiring together to firing together. J Physiol 552:1–11CrossRefPubMedGoogle Scholar
  38. Naber PA, Witter MP, Da Silva FHL (2000) Networks of the hippocampal memory system of the rat. The pivotal role of the subiculum. Ann NY Acad Sci 911:392–403PubMedCrossRefGoogle Scholar
  39. Nikizad H, Yon J-H, Carter LB, Jevtovic-Todorovic V (2007) Early exposure to general anesthesia causes significant neuronal deletion in the developing rat brain. Ann NY Acad Sci 1122:69–82CrossRefPubMedGoogle Scholar
  40. O’Mara SM, Commins S, Anderson M, Gigg J (2001) The subiculum: a review of form, physiology and function. Prog Neurobiol 64:129–155CrossRefPubMedGoogle Scholar
  41. Oo TF, Henchcliffe C, Burke RE (1995) Apoptosis in substantia nigra following developmental hypoxic-ischemic injury. Neuroscience 69:893–901CrossRefPubMedGoogle Scholar
  42. Oswald CJ, Good M (2000) The effects of combined lesions of the subicular complex and the entorhinal cortex on two forms of spatial navigation in the water maze. Behav Neurosci 114:211–217CrossRefPubMedGoogle Scholar
  43. Paxinos G, Watson C (1944) The rat brain in Stereotaxic coordinates. Academic Press, Sydney, AustraliaGoogle Scholar
  44. Peeling AN, Smart JL (1994) Successful prediction of immediate effects of undernutrition throughout the brain growth spurt on capillarity and synapse-to-neuron ratio of cerebral cortex in rats. Metab Brain Dis 9:81–95CrossRefPubMedGoogle Scholar
  45. Quimby KL, Aschkenase LJ, Bowman RE, Katz J, Chang LW (1974) Enduring learning deficits and cerebral synaptic malformation from exposure to 10 parts of halothane per million. Science 185:625–627CrossRefPubMedGoogle Scholar
  46. Rizzi S, Carter LB, Ori C, Jevtovic-Todorovic V (2008) Clinical anesthesia causes permanent damage to the fetal guinea pig brain. Brain Pathol 18:198–210CrossRefPubMedGoogle Scholar
  47. Slikker W Jr, Zou X, Hotchkiss CE, Divine RL, Sadovova N, Twaddle NC, Doerge DR, Scallet AC, Patterson TA, Hanig JP, Paule MG, Wang C (2007) Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol Sci 98:145–158CrossRefPubMedGoogle Scholar
  48. Sorensen SA, Jones TA, Olavarria JF (2003) Neonatal enucleation reduces the proportion of callosal boutons forming multiple synaptic contacts in rat striate cortex. Neurosci Lett 351:17–20CrossRefPubMedGoogle Scholar
  49. Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, Consiglio A, Van Praag H, Martone ME, Ellismann MH, Gage FH (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 6:727–734CrossRefGoogle Scholar
  50. Uemura E, Levin ED, Bowman RE (1985) Effects of halothane on synaptogenesis and learning behavior in rats. Exp Neurol 89:520–529CrossRefPubMedGoogle Scholar
  51. Uranova NA, Orlovskaya DD, Apel K, Klintsova AJ, Haselhorst U, Schenk H (1991) Morphometric study of synaptic patterns in the rat caudate nucleus and hippocampus under haloperidol treatment. Synapse 7:253–259CrossRefPubMedGoogle Scholar
  52. Waites CL, Craig AM, Garner CC (2005) Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci 28:251–274CrossRefPubMedGoogle Scholar
  53. Wooley CS, Wenzel HJ, Schwartzkroin PA (1996) Estradiol increase the frequency of multiple synapse boutons in the hippocampal CA1 region of the adult female rat. J Comp Neurol 373:108–117CrossRefGoogle Scholar
  54. Yankova M, Hart SA, Wooley CS (2001) Estrogen increases synaptic connectivity between single presynaptic inputs and multiple postsynaptic CA1 pyramidal cells: a serial electron-microscopic study. Proc Natl Acad Sci USA 98:3525–3530CrossRefPubMedGoogle Scholar
  55. Yon J-H, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic V (2005) Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience 35:815–827CrossRefGoogle Scholar
  56. Yon J-H, Carter LB, Reiter RJ, Jevtovic-Todorovic V (2006) Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis 21:522–530CrossRefPubMedGoogle Scholar
  57. Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J, Olney JW (2005) Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Brit J Pharmacol 146:189–197CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • N. Lunardi
    • 1
    • 2
    Email author
  • C. Ori
    • 2
  • A. Erisir
    • 3
    • 4
  • V. Jevtovic-Todorovic
    • 1
    • 4
  1. 1.Department of AnesthesiologyUniversity of Virginia Health SystemCharlottesvilleUSA
  2. 2.Department of Anesthesiology and PharmacologyUniversity of PadovaPadovaItaly
  3. 3.Department of PsychologyUniversity of VirginiaCharlottesvilleUSA
  4. 4.Department of NeuroscienceUniversity of VirginiaCharlottesvilleUSA

Personalised recommendations