Background: Neonatal exposure to anesthetics that block Nmethyl D-aspartate receptors and/or hyperactivate -aminobutyricacid type A receptor has been shown to cause neuronal degeneration in the developing brain, leading to functional deficits later in adulthood. The authors investigated whether exposure of neonatal mice to inhaled sevoflurane causes deficits in social behavior as well as learning disabilities.
Methods: Six-day-old C57BL/6 mice were exposed to 3% sevoflurane for 6 h. Activated cleaved caspase-3 immunohistochemical staining was used for detection of apoptosis. Cognitive functions were tested by pavlovian conditioned fear test. Social behavior was tested by social recognition and interaction tests.
Results: Neonatal exposure to sevoflurane significantly increased the number of apoptotic cells in the brain immediately after anesthesia. It caused persistent learning deficits later in adulthood as evidenced by decreased freezing response in both contextual and cued fear conditioning. The social recognition test demonstrated that mice with neonatal exposure to sevoflurane did not develop social memory. Furthermore, these mice showed decreased interactions with a social target compared with controls in the social interaction test, indicating a social interaction deficit. The authors did not attribute these abnormalities in social behavior to impairments of general interest in novelty or olfactory sensation, because they did not detect significant differences in the test for novel inanimate object interaction
or for olfaction.
Conclusions: This study shows that exposure of neonatal mice to inhaled sevoflurane could cause not only learning deficits but also abnormal social behaviors resembling autism spectrum disorder.
1. Bayer SA, Altman J, Russo RJ, Zhang X: Timetables of neurogenesis in the
human brain based on experimentally determined patterns in the rat. Neurotoxicology 1993; 14:83–144.
2. Rice D, Barone S Jr: Critical periods of vulnerability for the developing
nervous system: Evidence from humans and animal models. Environ Health
Perspect 2000; 108:511–33.
3. Olney JW, Tenkova T, Dikranian K, Qin YQ, Labruyere J, Ikonomidou C:
Ethanol-induced apoptotic neurodegeneration in the developing C57BL/6 mouse brain. Brain Res Dev Brain Res 2002; 133:115–26.
4. Dobbing J, Sands J: Comparative aspects of the brain growth spurt. Early
Hum Dev 1979; 3:79–83.
5. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K,
Zorumski CF, Olney JW, Wozniak DF: Early exposure to common anesthetic
agents causes widespread neurodegeneration in the developing rat brain and
persistent learning deficits. J Neurosci 2003; 23:876–82.
6. Fredriksson A, Ponte´n E, Gordh T, Eriksson P: Neonatal exposure to a
combination of N-methyl-D-aspartate and -aminobutyric acid type A receptor
anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. ANESTHESIOLOGY 2007; 107:427–36.
7. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Price
MT, Stefovska V, Ho¨rster F, Tenkova T, Dikranian K, Olney JW: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000; 287: 1056–60.
8. Lerman J, Sikich N, Kleinman S, Yentis S: The pharmacology of sevoflurane
in infants and children. ANESTHESIOLOGY 1994; 80:814–24.
9. Nishikawa K, Harrison NL: The actions of sevoflurane and desflurane on the
gamma-aminobutyric acid receptor type A: Effects of TM2 mutations in the alpha and beta subunits. ANESTHESIOLOGY 2003; 99:678–84.
10. Hollmann MW, Liu HT, Hoenemann CW, Liu WH, Durieux ME: Modulation of NMDA receptor function by ketamine and magnesium, part II: interactions with volatile anesthetics. Anesth Analg 2001; 92:1182–91.
11. Young C, Jevtovic-Todorovic V, Qin YQ, Tenkova T, Wang H, Labruyere J,
Olney JW: Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. Br J Pharmacol 2005; 146:189–97.
12. Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V: General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain. Apoptosis 2006; 11:1603–15.
13. Ito M, Nakashima M, Tsuchida N, Imaki J, Yoshioka M: Histogenesis of the
intravitreal membrane and secondary vitreous in the mouse. Invest Ophthalmol
Vis Sci 2007; 48:1923–30.
14. Satoh Y, Endo S, Ikeda T, Yamada K, Ito M, Kuroki M, Hiramoto T,
Imamura O, Kobayashi Y, Watanabe Y, Itohara S, Takishima K: Extracellular
signal-regulated kinase 2 (ERK2) knockdown mice show deficits in long-term
memory; Erk2 has a specific function in learning and memory. J Neurosci 2007; 27:10765–76.
15. Jin D, Liu HX, Hirai H, Torashima T, Nagai T, Lopatina O, Shnayder NA,
Yamada K, Noda M, Seike T, Fujita K, Takasawa S, Yokoyama S, Koizumi K,
Shiraishi Y, Tanaka S, Hashii M, Yoshihara T, Higashida K, Islam MS, Yamada N, Hayashi K, Noguchi N, Kato I, Okamoto H, Matsushima A, Salmina A, Munesue T, Shimizu N, Mochida S, Asano M, Higashida H: CD38 is critical for social behavior by regulating oxytocin secretion. Nature 2007; 446:41–5.
16. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y,
Baker SJ, Parada LF: Pten regulates neuronal arborization and social interaction in mice. Neuron 2006; 50:377–88.
17. Bittigau P, Sifringer M, Pohl D, Stadthaus D, Ishimaru M, Shimizu H, Ikeda M, Lang D, Speer A, Olney JW, Ikonomidou C: Apoptotic neurodegeneration
following trauma is markedly enhanced in the immature brain. Ann Neurol 1999; 45:724–35.
18. Wozniak DF, Hartman RE, Boyle MP, Vogt SK, Brooks AR, Tenkova T,
Young C, Olney JW, Muglia LJ: Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults. Neurobiol Dis 2004; 17:403–14.
19. Rosado JA, Lopez JJ, Gomez-Arteta E, Redondo PC, Salido GM, Pariente JA: Early caspase-3 activation independent of apoptosis is required for cellular function. J Cell Physiol 2006; 209:142–52.
20. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC:
Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like
ICE. Nature 1994; 371:346–7.
21. Kim JJ, Fanselow MS: Modality-specific retrograde amnesia of fear. Science
22. Phillips RG, LeDoux JE: Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 1992;
23. Murcia CL, Gulden F, Herrup K: A question of balance: A proposal for new
mouse models of autism. Int J Dev Neurosci 2005; 23:265–75.
24. Johnson SA, Young C, Olney JW: Isoflurane-induced neuroapoptosis in the
developing brain of nonhypoglycemic mice. J Neurosurg Anesthesiol 2008;
25. American Psychiatric Association: Diagnostic and Statistical Manual of
Mental Disorders, 4th ed. Washington, DC, American Psychiatric Association,
26. Moretti P, Bouwknecht JA, Teague R, Paylor R, Zoghbi HY: Abnormalities
of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet 2005; 14:205–20.
27. Lijam N, Paylor R, McDonald MP, Crawley JN, Deng CX, Herrup K, Stevens
KE, Maccaferri G, McBain CJ, Sussman DJ, Wynshaw-Boris A: Social interaction and sensorimotor gating abnormalities in mice lacking Dvl1. Cell 1997; 90:895–905.
28. Polleux F, Lauder JM: Toward a developmental neurobiology of autism.
Ment Retard Dev Disabil Res Rev 2004; 10:303–17.
29. Rubenstein JL, Merzenich MM: Model of autism: Increased ratio of excitation/ inhibition in key neural systems. Genes Brain Behav 2003; 5:255–67.
30. Uhlhaas PJ, Singer W: Neural synchrony in brain disorders: Relevance for
cognitive dysfunctions and pathophysiology. Neuron 2006; 52:155–68.
31. Buzsa´ki G, Draguhn A: Neuronal oscillations in cortical networks. Science
32. Hussman JP: Suppressed GABAergic inhibition as a common factor in
suspected etiologies of autism. Autism Dev Disord 2001; 2:247–8.
33. Bishop S, Gahagan S, Lord C: Re-examining the core features of autism: A
comparison of autism spectrum disorder and fetal alcohol spectrum disorder.
J Child Psychol Psychiatry 2007; 48:1111–21.
*Original abstract online at https://pubs.asahq.org/anesthesiology/article/110/3/628/10177/Neonatal-Exposure-to-Sevoflurane-Induces-Abnormal