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

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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.

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References

  • 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 263:146–158

    Article  CAS  PubMed  Google Scholar 

  • 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 45:724–735

    Article  CAS  PubMed  Google Scholar 

  • 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 997:137–146

    Article  CAS  PubMed  Google Scholar 

  • Chang LW, Dudley AW Jr, Lee YK, Katz J (1974) Ultrastructural changes in the nervous system after chronic exposure to halothane. Exp Neurol 45:209–219

    Article  CAS  PubMed  Google Scholar 

  • Chang LW, Dudley AW Jr, Katz J (1976) Pathological changes in the nervous system following in utero exposure to halothane. Environ Res 11:40–51

    Article  CAS  PubMed  Google Scholar 

  • 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 29:1150–1160

    Article  PubMed  Google Scholar 

  • 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 63:195–204

    Article  CAS  PubMed  Google Scholar 

  • 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 9:251–259

    Article  CAS  PubMed  Google Scholar 

  • 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 960:9–15

    Article  CAS  PubMed  Google Scholar 

  • 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 502:261–274

    Article  CAS  PubMed  Google Scholar 

  • 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 23:5208–5218

    CAS  PubMed  Google Scholar 

  • Franks NP (2008) General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 9:370–386

    Article  CAS  PubMed  Google Scholar 

  • 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 96:1–12

    Article  CAS  PubMed  Google Scholar 

  • Garcia JH, Lassen NA, Weiller C, Sperling B, Nakagawara J (1996) Ischemic stroke and incomplete infarction. Stroke 27:761–765

    CAS  PubMed  Google Scholar 

  • 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 39:991–999

    Article  CAS  PubMed  Google Scholar 

  • 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 7:301–308

    Article  CAS  PubMed  Google Scholar 

  • 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 283:70–74

    Article  CAS  PubMed  Google Scholar 

  • 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 287:1056–1060

    Article  CAS  PubMed  Google Scholar 

  • 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 28:3427–3437

    Article  CAS  PubMed  Google Scholar 

  • 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 4:460–463

    Article  CAS  PubMed  Google Scholar 

  • 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 130:1692–1698

    Article  CAS  PubMed  Google Scholar 

  • 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 23:876–882

    CAS  PubMed  Google Scholar 

  • Jonas E (2004) Regulation of synaptic transmission by mitochondrial ion channels. J Bioenerg Biomembr 36:357–361

    Article  CAS  PubMed  Google Scholar 

  • 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 16:814–825

    Article  CAS  PubMed  Google Scholar 

  • 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 1022:101–109

    Article  PubMed  CAS  Google Scholar 

  • 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 24:10191–10200

    Article  CAS  PubMed  Google Scholar 

  • Laxmi TR, Bindu PN, Raju TR, Meti BL (1999) Spatial memory impairment in ventral subicular lesioned rats. Brain Res 816:245–248

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Okamoto K, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119:873–887

    Article  CAS  PubMed  Google Scholar 

  • 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 15:393–403

    Article  PubMed  Google Scholar 

  • Lodge D, Anis NA (1982) Effects of phencyclidine on excitatory amino acid activation of spinal interneurones in the cat. Eur J Pharmacol 77:203–204

    Article  CAS  PubMed  Google Scholar 

  • 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 108:90–104

    Article  CAS  PubMed  Google Scholar 

  • Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V (2006) General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 11:1603–1615

    Article  CAS  PubMed  Google Scholar 

  • McNaughton N (2006) The role of the subiculum within the behavioural inhibition system. Behav Brain Res 174:232–250

    Article  CAS  PubMed  Google Scholar 

  • 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 18:9716–9726

    CAS  PubMed  Google Scholar 

  • Mody I (2005) Aspects of the homeostatic plasticity of GABAA receptor-mediated inhibition. J Physiol. 562:37–46

    Article  CAS  PubMed  Google Scholar 

  • 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 2:1016–1028

    Article  PubMed  Google Scholar 

  • Munno DW, Syed NI (2003) Synaptogenesis in the CNS: an odyssey from wiring together to firing together. J Physiol 552:1–11

    Article  CAS  PubMed  Google Scholar 

  • 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 911:392–403

    Article  CAS  PubMed  Google Scholar 

  • 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 1122:69–82

    Article  CAS  PubMed  Google Scholar 

  • O’Mara SM, Commins S, Anderson M, Gigg J (2001) The subiculum: a review of form, physiology and function. Prog Neurobiol 64:129–155

    Article  PubMed  Google Scholar 

  • Oo TF, Henchcliffe C, Burke RE (1995) Apoptosis in substantia nigra following developmental hypoxic-ischemic injury. Neuroscience 69:893–901

    Article  CAS  PubMed  Google Scholar 

  • 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 114:211–217

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1944) The rat brain in Stereotaxic coordinates. Academic Press, Sydney, Australia

    Google Scholar 

  • 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 9:81–95

    Article  CAS  PubMed  Google Scholar 

  • 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 185:625–627

    Article  CAS  PubMed  Google Scholar 

  • Rizzi S, Carter LB, Ori C, Jevtovic-Todorovic V (2008) Clinical anesthesia causes permanent damage to the fetal guinea pig brain. Brain Pathol 18:198–210

    Article  PubMed  Google Scholar 

  • 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 98:145–158

    Article  CAS  PubMed  Google Scholar 

  • 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 351:17–20

    Article  CAS  PubMed  Google Scholar 

  • 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 6:727–734

    Article  CAS  Google Scholar 

  • Uemura E, Levin ED, Bowman RE (1985) Effects of halothane on synaptogenesis and learning behavior in rats. Exp Neurol 89:520–529

    Article  CAS  PubMed  Google Scholar 

  • 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 7:253–259

    Article  CAS  PubMed  Google Scholar 

  • Waites CL, Craig AM, Garner CC (2005) Mechanisms of vertebrate synaptogenesis. Annu Rev Neurosci 28:251–274

    Article  CAS  PubMed  Google Scholar 

  • 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 373:108–117

    Article  Google Scholar 

  • 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 98:3525–3530

    Article  CAS  PubMed  Google Scholar 

  • 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 35:815–827

    Article  CAS  Google Scholar 

  • 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 21:522–530

    Article  CAS  PubMed  Google Scholar 

  • 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 146:189–197

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations

  1. Department of Anesthesiology, University of Virginia Health System, PO Box 800710, Charlottesville, VA, 22908, USA

    N. Lunardi & V. Jevtovic-Todorovic

  2. Department of Anesthesiology and Pharmacology, University of Padova, Padova, Italy

    N. Lunardi & C. Ori

  3. Department of Psychology, University of Virginia, Charlottesville, VA, USA

    A. Erisir

  4. Department of Neuroscience, University of Virginia, Charlottesville, VA, USA

    A. Erisir & V. Jevtovic-Todorovic

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  1. N. Lunardi
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  2. C. Ori
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  3. A. Erisir
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  4. V. Jevtovic-Todorovic
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Correspondence to N. Lunardi.

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Lunardi, N., Ori, C., Erisir, A. et al. General Anesthesia Causes Long-Lasting Disturbances in the Ultrastructural Properties of Developing Synapses in Young Rats. Neurotox Res 17, 179–188 (2010). https://doi.org/10.1007/s12640-009-9088-z

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