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