Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats

Abstract

Propofol is a general anesthetic commonly used in pediatric clinical practices. Experimental findings demonstrate that anesthetics induce widespread apoptosis and cognitive decline in a developing brain. Although anesthesia-mediated neurotoxicity is the most prominent during intense period of synaptogenesis, the effects of an early anesthesia exposure on the synapses are not well understood. The aim of this study was to examine the effects of neonatal propofol anesthesia on the expression of key proteins that participate in synaptogenesis and synaptic plasticity and to evaluate long-term neurobehavioral abnormalities in the mature adult brain. Propofol-injected 7-day-old rats were maintained under 2-, 4-, and 6-h-long anesthesia and sacrificed 0, 4, 16, and 24 h after the termination of each exposure. We showed that propofol anesthesia strongly influenced spatiotemporal expression and/or proteolytic processing of crucial presynaptic (GAP-43, synaptophysin, α-synuclein), trans-synaptic (N-cadherin), and postsynaptic (drebrin, MAP-2) proteins in the cortex and thalamus. An overall decrease of synaptophysin, α-synuclein, N-cadherin, and drebrin indicated impaired function and structure of the synaptic contacts immediately after anesthesia cessation. GAP-43 and MAP-2 adult and juvenile isoforms are upregulated following anesthesia, suggesting compensatory mechanism in the maintaining of the structural integrity and stabilization of developing axons and dendritic arbors. Neonatal propofol exposure significantly altered spontaneous motor activity (increased stereotypic/repetitive movements) and changed emotional behavior (reduced anxiety-like response) in the adulthood, 6 months later. These findings suggest that propofol anesthesia is synaptotoxic in the developing brain, disturbing synaptic dynamics and producing neuroplastic changes permanently incorporated into existing networks with long-lasting functional consequences.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. Al-Jahdari WS, Saito S, Nakano T, Goto F (2006) Propofol induces growth cone collapse and neurite retraction in chick explant culture. Can J Anaesth 53:1078–1085

    Article  Google Scholar 

  2. Balakrishnan B, Dai H, Janisse J, Romero R, Kannan S (2013) Maternal endotoxin exposure results in abnormal neuronal architecture in the newborn rabbit. Dev Neurosci 35:396–405

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Barry S, Baird G, Lascelles K, Bunton P, Hedderly T (2011) Neurodevelopmental movement disorders—an update on childhood motor stereotypies. Dev Med Child Neurol 53:979–985

    Article  PubMed  Google Scholar 

  4. Bellani S, Sousa VL, Ronzitti G, Valtorta F, Meldolesi J, Chieregatti E (2010) The regulation of synaptic function by α-synuclein. Commun Integr Biol 3:106–109

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bercker S, Bert B, Bittigau P, Felderhoff-Müser U, Bührer C, Ikonomidou C, Weise M, Kaisers UX, Kerner T (2009) Neurodegeneration in newborn rats following propofol and sevoflurane anesthesia. Neurotox Res 16, 2:140–147

  6. Boyd BA, Baranek GT, Sideris J, Poe M, Watson LR, Patten E, Miller H (2010) Sensory features and repetitive behaviors in children with autism and developmental delays. Autism Res 3:78–87

    PubMed  PubMed Central  Google Scholar 

  7. Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L (2011) Developmental stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 115:282–293

    CAS  Article  PubMed  Google Scholar 

  8. Chen B, Deng X, Wang B, Liu H (2016) Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats. J Toxicol Sci 41(5):627–636

    Article  PubMed  Google Scholar 

  9. Cheng F, Vivacqa G, Yu S (2011) The role of alpha-synuclein in neurotransmission and synaptic plasticity. J Chem Neuroanatomy 42:242–248

    CAS  Article  Google Scholar 

  10. Chimura T, Launey T, Yoshida N (2015) Calpain-mediated degradation of drebrin by excitotoxicity in vitro and in vivo. PLoS One 10(4):e0125119. doi:137/journal.pone.0125119

  11. Cotter DI, Wilson S, Roberts E, Kerwin R, Everall IP (2000) Increased dendritic MAP2 expression in the hippocampus in schizophrenia. Schizophr Res 41:313–323

    CAS  Article  PubMed  Google Scholar 

  12. Counts SE, Nadeem M, Lad SP, Wuu J, Mufson EJ (2006) Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment. J Neuropathol Exp Neurol 65:592–601

    CAS  Article  PubMed  Google Scholar 

  13. Dalla Massara L, Osuru HP, Oklopcic A, Milanovic D, Joksimovic SM, Caputo V, DiGruccio MR, Ori C, Wang G, Todorovic SM, Jevtovic-Todorovic V (2016) General anesthesia causes epigenetic histone modulation of c-fos and brain-derived neurotrophic factor, target genes important for neuronal development in the immature rat hippocampus. Anesthesiology 124:1311–1327

    CAS  Article  PubMed  Google Scholar 

  14. De Roo M, Klauser P, Briner A, Nikonenko I, Mendez P, Dayer A, Kiss JZ, Muller D, Vutskits L (2009) Anesthetics rapidly promote synaptogenesis during a critical period of brain development. PLoS One 4(9):e7043. doi:10.1371/journal.pone.0007043

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dehmelt L, Smart FM, Ozer RS, Halpain S (2003) The role of microtubule-associated protein 2c in the reorganization of microtubules and lamellipodia during neurite initiation. J Neurosci 23(29):9479–9490

    CAS  PubMed  Google Scholar 

  16. Denny JB (2006) Molecular mechanisms, biological actions, and neuropfaramacology of the growth-associated proteib GAP-43. Curr Neuropharmacol 4:293–304

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Dufty BM, Warner LR, Hou ST, Jiang SX, Gomez-Isla T, Leenhouts KM, Oxfrord JT, Feany MB, Masliah E, Rohn TT (2007) Calpain-cleavage of a-synuclein. Amer J Pathol 170:1725–1738

    CAS  Article  Google Scholar 

  18. Dunican DJ, Doherty P (2000) The generation of localized calcium rises mediated by cell adhesion molecules and their role in neuronal growth cone motility. Mol Cell Biol Res Comm 3:255–263

    CAS  Article  Google Scholar 

  19. Evans GJO, Cousin MA (2005) Tyrosine phosphorylation of synaptophysin in synaptic vesicle recycling. Biochem Soc Trans 33:1350–1353

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Fifre A, Sponne I, Koziel V, Kriem B, Potin FTY, Bihain BE, Olivier JL, Oster T, Pillot T (2006) Microtubule-associated protein MAP1, MAP1B, and MAP2 proteolysis during soluble amyloid β-peptide-induced neuronal apoptosis. J Biol Chem 281:229–240

    CAS  Article  PubMed  Google Scholar 

  21. Fredriksson A, Pontén E, Gordh T, Eriksson P (2007) Neonatal exposure to a combination of N-methyl-D-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 107(3):427–436

    CAS  Article  PubMed  Google Scholar 

  22. Gao J, Peng S, Xiang S, Huang J, Chen P (2014) Repeated exposure to propofol impairs spatial learning, inhibits LTP and reduces CaMKIIa in rats. Neurosci Lett 560:62–66

    CAS  Article  PubMed  Google Scholar 

  23. Gonzales ELT, Yang SM, Choi CS, Mabunga DFN, Kim HJ, Cheong JH, Ryu JH, Koo BN, Shin CY (2015) Repeated neonatal propofol administration induces sex-dependent long-term impairments on spatial and recognition memory in rats. Biomol Ther 23:251–260

    CAS  Article  Google Scholar 

  24. Han MH, Jiao S, Jia JM, Chen Y, Vhen CY, Gucek M, Markey SP, Li Z (2013) The novel caspase-3 substrate Gap43 is involved in AMPA receptor endocytosis and long-term depression. Mol Cell Proteomics 12:3719–3731

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Han D, Jin J, Fang H, Xu G (2015) Long-term action of propofol on cognitive function and hippocampal neuroapoptosis in neonatal rats. Int J Clin Exp Med 8:10696–10704

    PubMed  PubMed Central  Google Scholar 

  26. Hoskison MM, Shuttleworth CW (2006) Microtubule disruption, not calpain-dependent loss of MAP2, contributes to enduring NMDA-induced dendritic dysfunction in acute hippocampal slices. Exp Neurol 202:302–312

    CAS  Article  PubMed  Google Scholar 

  27. Huang L, Yang G (2015) repeated exposure to ketamine-xylazine during early developmental impairs motor learning-dependent dendritic spine plasticity in adulthood. Anethseiology 122(4):821-831

  28. Ivanov A, Esclapez M, Pellegrino C, Shirao T, Ferhat L (2009) Drebrin A regulates dendritic spine plasticity and synaptic function in mature cultured hippocampal neurons. J Cell Sci 122:524–534

    CAS  Article  PubMed  Google Scholar 

  29. Jackson JJ, Andrews N, Ball D, Bellantuono I, Gray J, Hachoumi L, Holmes A, Latcham J, Petrie A, Potter P, Rice A, Ritchie A, Stewart M, Strepka C, Yeoman M, Chapman K (2016) Does age matter? The impact of rodent age on study outcome. Lab Anim 1–9, DOI: 10.1177/0023677216653984

  30. Jalavaa NS, Lopez-Picona FR, Kukko-Lukjanov TK, Holopainena IE (2007) Changes in microtubule-associated protein-2 (MAP2) expression during development and after status epilepticus in the mmature rat hippocampus. Inter J Dev Neurosci 25:121–131

    Article  Google Scholar 

  31. Jang S-S, Chung HJ (2016) Emerging link between Alzheimer’s disease and homeostatic synaptic plasticity. Neural Plast 2016:7969272. doi:10.1155/2016/7969272

    PubMed  PubMed Central  Google Scholar 

  32. Jang Y-N, Jung Y-S, Moon C-H, Kim C-H, Baik EJ (2009) Calpain-mediated N-cadherin proteolytic processing in brain injury. J Neurosci 29:5974–5984

    CAS  Article  PubMed  Google Scholar 

  33. 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(3):876-82

  34. Jevtovic-Todorovic V, Absalam AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, Fiskum G, Giffard RG, Herold KF, Loepke AW, Ma D, Orser BA, Planel E, Slikker W, Soriano SG, Stratmann G, Vutskits L, Hemming HC (2010) Anaesthetic neurotoxicity and neuroplasticity; an expert group report and statement based on the BJA Salzburg seminar. Brit J Anaesth 111:143–151

    Article  Google Scholar 

  35. Karen T, Schlager GW, Bendix I, Sifringer M, Herrmann R, Pantazis C, Enot D, Keller M, Kerner T, Felderhoff-Mueser U (2013) Effect of propofol in the immature rat brain on short- and long-term neurodevelopmental outcome. PLoS One 8(5):e64489. doi:10.1371/journal.pone.0064480

    Article  Google Scholar 

  36. Kojima N, Shirao T (2007) Synaptic dysfunction and disruption of postsynaptic drebrin-actin complex: a study of neurological disorder accompanied by cognitive deficits. Neurosci Res 58:1–5

    CAS  Article  PubMed  Google Scholar 

  37. Koleske AJ (2013) Molecular mechanisms of dendrite stability. Nature RevNeurosci 14:536–550

    CAS  Google Scholar 

  38. Latefi NS, Pedraza L, Schohl A, Li Z, Ruthazer ES (2009) N-cadherin prodomain cleavage regulates synapse formation in vivo. Dev Neurobiol 69:518–529

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Leclerc N, Baas PW, Garner CC, Kosik KS (1996) Juvenile and mature MAP2 isofroms induce distinct patterns of process outgrowth. Molec Biol Cell 7:443–455

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Leitner Y (2014) The co-occurrence of autism and attention deficit hyperactivity disorder in children—what do we know? Front Hum Neurosci 3:78–87. doi:10.1002/aur.124

    Google Scholar 

  41. Li J, Xiong M, Nadavaluru PR, Zuo W, Ye JH, Eloy JD, Bekker A (2016) Dexmedetomidine attenuates neurotoxicity induced by prenatal propofol exposure. J Neurosurg Anesthesiol 28(1):51–64

    CAS  Article  PubMed  Google Scholar 

  42. Lunardi N, Oklopcic A, Prillaman M, Erisier A, Jevtovic-Todorovic V (2015) Early exposure to general anesthesia disrupts spatial organization of presynaptic vesicles in nerve terminals of the developing rat subiculum. Mol Neurobiol 52:942–951

    CAS  Article  PubMed  Google Scholar 

  43. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK (2003) A CBP binding transcriptional repressor produced by the PS1/ε-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114:635–645

    CAS  Article  PubMed  Google Scholar 

  44. Mattson MP, Keller JN, Begley JG (1998) Evidence for synaptic apoptosis. Exp Neurol 153:35–48

    CAS  Article  PubMed  Google Scholar 

  45. Mendez P, De Roo M, Paglia L, Klauser P, Muller D (2010) N-cadherin mediates plasticity-induced long-term spine stabilization. J Cell Biol 189:589–600

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Meyer MP, Smith SJ (2006) Evidence from in vivo imaging that synaptogenesis guides the growth and branching of axonal arbors by two distinct mechanisms. J Neurosci 26(13):3604–3614

    CAS  Article  PubMed  Google Scholar 

  47. Milanovic D, Popic J, Pesic V, Loncarevic-Vasiljkovic N, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2010) Regional and temporal profiles of calpain and caspase-3 activities in postnatal rat brain following repeated propofol administration. Dev Neurosci 32:288–301

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Milanovic D, Pesic V, Popic J, Tanic N, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2014) Propofol anesthesia induces proapoptotic tumor necrosis factor-α and pro-nerve growth factor signaling as well as prosurvival Akt and XIAP expression in neonatal rat brain. J Neurosci Res 92:1362–1373

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Milanovic D, Pesic V, Loncarevic-Vasiljkovic N, Pavkovic Z, Popic J, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2016) The Fas ligand/Fas death receptor pathways contribute to propofol-induced apoptosis and neuroinflammation in the brain of neonatal rats. Neurotox Res 30:434–452

    CAS  Article  PubMed  Google Scholar 

  50. Miller FD, Kaplan DR (2003) Signaling mechanisms underlying dendrite formation. Curr Opin Neurobiol 13:391–398

    CAS  Article  PubMed  Google Scholar 

  51. Ming X, Jing L, Alhashem HM, Tilak V, Patel A, Pisklakov S, Siegel A, Jiang HY, Bekker A (2014) Propofol exposure in pregnant rats induces neurotoxicity and persistent learning deficit in the offspring. Brain Sci 492:356–375

    Google Scholar 

  52. Murphy DD, Rueter SM, Trojanowski JQ, Lee VMY (2000) Synucleins are developmentally expressed, and a-synuclein regulates the size of the presynaptic pool in primary hippocampal neurons. J Neurosci 20:3214–3220

    CAS  PubMed  Google Scholar 

  53. Nakao S, Nagata S, Miyamoto E, Masuzawa M, Murayama T, Shingu K (2003) Inhibitory effect of propofol on ketamine-induced c-Fos expression in the rat posterior cingulated and retrosplenial cortices is mediated by GABAA receptor activation. Acta Anesthesiol Scand 47:284–290

    CAS  Article  Google Scholar 

  54. Niell CM, Meyer MP, Smith SJ (2004) In vivo imaging of synapse formation on a growing dendritic arbor. Nat Neurosci 7:254–260

    CAS  Article  PubMed  Google Scholar 

  55. 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 N Y Acad Sci 1122:69–82

    CAS  Article  PubMed  Google Scholar 

  56. Oscarsson A, Massoumi R, Sjolander A, Eintrei C (2001) Reorganization of actin in neurons after propofol exposure. Acta Anesthesiol Scand 45:1215–1220

    CAS  Article  Google Scholar 

  57. Pearn ML, Hu Y, Niesman IR, Patel HH, Drummond JC, Roth DM, Akassoglou K, Patel PM, Head BP (2012) Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation. Anesthesiology 116:352–361

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Penzes P, Cahill ME, Jones KA, VanLeeuwen J-E, Woolfrey KM (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14:285–293

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Pesic V, Milanovic D, Tanic N, Popic J, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2009) Potential mechanism of cell death in the developing rat brain induced by propofol anesthesia. Int J Dev Neurosci 27:279–287

    CAS  Article  PubMed  Google Scholar 

  60. Pesic V, Milanovic D, Popic J, Smiljanic K, Tesic V, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S (2015) Neonatal propofol anesthesia modifies activity-dependent processes and induces transient hyperlocomotor response to D-amphetamine during adolescence in rats. Int J Dev Neurosci 47:266–277

    CAS  Article  PubMed  Google Scholar 

  61. Platholi J, Herold KF, Hemmings HC Jr, Halpain S (2014) Isoflurane reversibly destabilizes hippocampal dendritic spines by an actin-dependent mechanisms. PLoS One 9(7):e102978. doi:10.1371/journal.pone.0102978

    Article  PubMed  PubMed Central  Google Scholar 

  62. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (2006) Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 26(27):7212–7221

    CAS  Article  PubMed  Google Scholar 

  63. Reines A, Bernier LP, McAdam R, Belkaid W, Shan W, Koch AW, Seguela P, Colman DR, Dhaunchak AS (2012) N-cadherin prodomain processing regulates synaptogenesis. J Neurosci 32:6323–6334

    CAS  Article  PubMed  Google Scholar 

  64. Rizzi S, Ori C, Jevtovic-Todorovic V (2010) Timing versus duration: determinants of anesthesia-induced developmental apoptosis in the young mamalian brain. Ann N Y Acad Sci 1199:43–51

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. Rosenberg T, Gal-Ben-Ari S, Dieterich DC, Kreutz MR, Ziv NE, Gundelfinger ED, Rosenblum K (2014) The roles of protein expression in synaptic oplasticity and memory consolidation. Front Neurosci 7:86. doi:10.3389/fnmol.2014.00086

    Google Scholar 

  66. Sanchez V, Feinstein SD, Lunardi N, Joksovic PM, Boscolo A, Todorovic SM, Jevtovic-Todorovic V (2011) General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology 115:992–1002

    Article  PubMed  PubMed Central  Google Scholar 

  67. Schaefers ATU, Teuchert-Noodt G (2013) Developmental neuroplasticity and the origin of neurodegenerative diseases. World J Biol Psychiatry. doi:10.3109/15622975.2013.797104

    PubMed  Google Scholar 

  68. Sengupta P (2011) A scientific review of age determination for a laboratory rat: how old is it in comparison with human age? Biomed Inter 2:81–89

    Google Scholar 

  69. Sernagor E, Chabrol F, Bony G, Cancedda L (2010) GABAergic control of neurite outgrowth and remodeling during development and adult neurogenesis: general rules and differences in diverse systems. Front Cell Neurosci 4:1–11

    Article  Google Scholar 

  70. Sheng M, Kim E (2012) The postsynaptic organization of synapses. Cold Spring Harb Perscept Biol 3:a005678

    Google Scholar 

  71. Shih J, May LV, Gonzalez HE, Lee EW, Alvi RS, Sall JW, Rau V, Bickler PE, Lalchandani GR, Ysupova M, Woodward E, Kang H, Wilk AJ, Carlston CM, Mendoza MV, Guggenheim JN, Schaefer M, Rowe AM, Stratmann G (2012) Delayed environmental enrichment reverses sevoflurane-induced memory impairment in rats. Anesthesiology 116(3):586–602

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Singer HS (2009) Motor stereotypies. Semin Pediatr Neurol 16:77–81

    Article  PubMed  Google Scholar 

  73. Sitditkova G, Zakharov A, Janackova S, Gerasimova E, Lebedeva J, Inacio AR, Zaynutdinova D, Minlebaev M, Holmes G, Khazipov R (2013) Isoflurane suppresses early cortical activity. Ann Clinic Translat Neurol 1:15–26

    Article  Google Scholar 

  74. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci and Biobehav Rev 24:417–463

    CAS  Article  Google Scholar 

  75. Sprung J, Flick RP, Katusic S, Colligan RC, Barbaresi WJ, Bojanic K, Welch TL, Olson MD, Hanson AC, Schroeder DR, Wilder RT, Warner DO (2012) Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 87:120–129

    Article  PubMed  PubMed Central  Google Scholar 

  76. Stoeckli ET (2012) What does the developing brain tell us about neural diseases? Eur J Neurosci 35:1811–1817

    Article  PubMed  Google Scholar 

  77. Stratmann G, Sall JW, May LD, Loepke AW, Lee MI (2010) Beyond anesthetic properties: the effects of isoflurane on brain cell death, neurogenesis, and long-term neurocognitive function. Anesth Analg 110(2):431–437

    CAS  Article  Google Scholar 

  78. Sun N, Tischfield JA, King RA, Heiman GA (2016) Functional evaluation of genes disrupted in patients with Tourette’s disorder. Front Psychiatry 7:11. doi:10.3389/fpsyt.2016.00011

    PubMed  PubMed Central  Google Scholar 

  79. Tada T, Sheng M (2008) Molecular mechanisms of dendritic spine morphogenesis. Curr Opin Neurobiol 16:95–101

    Article  Google Scholar 

  80. Tai C-Y, Kim SA, Schuman EM (2008) Cadherins and synaptic plasticity. Curr Opin Cell Biol 20:567–575

    CAS  Article  PubMed  Google Scholar 

  81. Takeichi M, Abe K (2005) Synaptic contact dynamics controlled by cadherin and catenins. Trends Cell Biol 15:216–221

    CAS  Article  PubMed  Google Scholar 

  82. Thompson SN, Gibson TR, Thompson BM, Deng Y, Hall ED (2006) Relationship of calpain-mediated proteolysis to the expression of axonal and synaptic plasticity markers following traumatic brain injury in mice. Exp Neurol 201:253–265

    CAS  Article  PubMed  Google Scholar 

  83. Turina D, Loitto VM, Bjornstrom K, Sundqvist T, Eintrei C (2008) Propofol causes neurite retraction in neurones. Brit J Anaesth 101:374–379

    CAS  Article  PubMed  Google Scholar 

  84. Vutskits L (2012) General anesthesia: a gateway to modulate synapse formation and neural plasticity? Anesth Analg 115:1174–1181

    CAS  Article  PubMed  Google Scholar 

  85. Vutskits L, Gascon E, Tassonyi E, Kiss JZ (2005) Clinically relevant concentrations of propofol but not midazolam alter in vitro dendritic development of isolated gamma-aminobutyric acid-positive interneurons. Anesthesiology 102:970–976

    CAS  Article  PubMed  Google Scholar 

  86. Wallas SI, Jahn R, Greengard P (1988) Quantification of nerve terminal populations: synaptic vesicle-associated proteins as markers for synaptic density in the rat striatum. Synapse 2950:516–520

    Article  Google Scholar 

  87. Wang YL, Chen X, Wang ZP (2015) Detrimental effects of postnatal exposure to propofol on memory and hippocampal LTP in mice. Brain Res 1622:321–327

    CAS  Article  PubMed  Google Scholar 

  88. Wang Y, Wu C, Han B, Mao M, Guo X, Wang J (2016) Dexmedetomidine attenuates repeated propofol exposure-induced hippocampal apoptosis, PI3K/Akt/Gsk-3β signaling disruption, and juvenile cognitive deficits in neonatal rats. Mol Med Rep 14:769–775

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Weigt HU, Georgieff M, Beyer C, Föhr KJ (2002) Activation of neuronal N-methyl-D-aspartate receptor channels by lipid emulsions. Anesth Analg 94:331–337

    CAS  Article  PubMed  Google Scholar 

  90. Wilder RT (2010) Is there any relationship between long-term behavior disturbance and early exposure to anesthesia? Curr Opin Anaesth 23:332–336

    Article  Google Scholar 

  91. Xu C, Seubert CN, Gravenstein N, Martynyuk AE (2016) Propofol, but not etomidate, increases corticosterone levels and induces long-term alteration in hippocampal synaptic activity in neonatal rats. Neurosci Lett 618:1–5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Yam PT, Pincus Z, Gupta GD, Bashkurov M, Charron F, Pelletier L, Colman DR (2013) N-cadherin relocalizes from the periphery to the center of the synapse after transient synaptic stimulation in hippocampal neurons. PLoS One 8(11):e79679. doi:10.1371/journal.pone.0079679

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. Yu D, Jiang Y, Gao J, Liu B, Chen P (2013) Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats. Neurosci Lett 534:41–46

    CAS  Article  PubMed  Google Scholar 

  94. Zakharov VV, Mosevitsky MI (2007) M-calpain-mediated cleavage og GAP-43 near Ser41 is negatively regulated by protein kinase C, calmodulin and calpain-inhibiting fragment GAP-43-3. J Neuroch 101:1539–1551

    CAS  Article  Google Scholar 

  95. Zhong L, Luo F, Zhao W, Feng Y, Wu L, Lin J, Liu T, Wang S, You X, Zhang W (2016) Propofol exposure during late stages of pregnancy impairs learning and memory in rat offspring via the BDNF-TrkB signalling pathway. J Cell Mol Med 20:1920–1931

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant ON173056 from the Ministry of Education, Science and Technological Development of the Republic of Serbia.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Desanka Milanovic or Sabera Ruzdijic.

Ethics declarations

All experimental procedures were in compliance with the EEC Directive (86/609/EEC) on the protection of animals used for experimental and other scientific purposes and were approved by the Ethical Committee for the Use of Laboratory Animals of the Institute for Biological Research, University of Belgrade, and in accordance with the Guide for the Care and Use of Laboratory Animals (NIH).

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Milanovic, D., Pesic, V., Loncarevic-Vasiljkovic, N. et al. Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats. Neurotox Res 32, 247–263 (2017). https://doi.org/10.1007/s12640-017-9730-0

Download citation

Keywords

  • Developing brain
  • Propofol anesthesia
  • Synaptic plasticity
  • Behavior
  • Neurotoxicity