Neonatal Propofol Anesthesia Changes Expression of Synaptic Plasticity Proteins and Increases Stereotypic and Anxyolitic Behavior in Adult Rats
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.
KeywordsDeveloping brain Propofol anesthesia Synaptic plasticity Behavior Neurotoxicity
This work was supported by Grant ON173056 from the Ministry of Education, Science and Technological Development of the Republic of Serbia.
Compliance with Ethical Standards
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.
- 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, 2:140–147Google Scholar
- 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
- 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 124:1311–1327CrossRefPubMedGoogle Scholar
- 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):427–436CrossRefPubMedGoogle Scholar
- 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):821-831Google Scholar
- 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
- 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):876-82Google Scholar
- 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 111:143–151CrossRefGoogle Scholar
- Koleske AJ (2013) Molecular mechanisms of dendrite stability. Nature RevNeurosci 14:536–550Google Scholar
- 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 32:288–301CrossRefPubMedPubMedCentralGoogle Scholar
- 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 92:1362–1373CrossRefPubMedPubMedCentralGoogle Scholar
- 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 30:434–452CrossRefPubMedGoogle Scholar
- 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 492:356–375Google Scholar
- 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 47:266–277CrossRefPubMedGoogle Scholar
- Sengupta P (2011) A scientific review of age determination for a laboratory rat: how old is it in comparison with human age? Biomed Inter 2:81–89Google Scholar
- Sheng M, Kim E (2012) The postsynaptic organization of synapses. Cold Spring Harb Perscept Biol 3:a005678Google Scholar
- 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):586–602CrossRefPubMedPubMedCentralGoogle Scholar
- 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 87:120–129CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar