Developmental Stage-dependent Persistent Impact of Propofol Anesthesia on Dendritic Spines in the Rat Medial Prefrontal Cortex

Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland.
Anesthesiology (Impact Factor: 5.88). 06/2011; 115(2):282-93. DOI: 10.1097/ALN.0b013e318221fbbd
Source: PubMed


Recent observations demonstrate that anesthetics rapidly impair synaptogenesis during neuronal circuitry development. Whether these effects are lasting and depend on the developmental stage at which these drugs are administered remains, however, to be explored.
Wistar rats received propofol anesthesia at defined developmental stages during early postnatal life. The acute and long-term effects of these treatments on neuronal cytoarchitecture were evaluated by Neurolucida and confocal microscopy analysis after iontophoretic injections of Lucifer Yellow into layer 5 pyramidal neurons in the medial prefrontal cortex. Quantitative electron microscopy was applied to investigate synapse density.
Layer 5 pyramidal neurons of the medial prefrontal cortex displayed intense dendritic growth and spinogenesis during the first postnatal month. Exposure of rat pups to propofol at postnatal days 5 and 10 significantly decreased dendritic spine density, whereas this drug induced a significant increase in spine density when administered at postnatal days 15, 20, or 30. Quantitative electron microscopy revealed that the propofol-induced increase in spine density was accompanied by a significant increase in the number of synapses. Importantly, the propofol-induced modifications in dendritic spine densities persisted up to postnatal day 90.
These new results demonstrate that propofol anesthesia can rapidly induce significant changes in dendritic spine density and that these effects are developmental stage-dependent, persist into adulthood, and are accompanied by alterations in synapse number. These data suggest that anesthesia in the early postnatal period might permanently impair circuit assembly in the developing brain.

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    • "Several experimental studies have demonstrated that propofol causes widespread apoptosis in the developing brain and leads to long-term behavioral deficits (Cattano et al., 2008; Pearn et al., 2012; Yu et al., 2013). Furthermore , recent studies suggest that propofol induces alterations in synaptogenesis, including changes in dendritic growth (Vutskits et al., 2005), dendritic spine density and synapse number (Briner et al., 2011). Synaptogenesis correlates with several types of proteins , including myelin basic protein (MBP), which is an important component of the myelin sheath that enwraps axons (Brosamle and Halpern, 2002). "
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    ABSTRACT: Anesthetics can cause widespread apoptotic neurodegeneration and adverse effects on synaptogenesis during early postnatal life. Synaptogenesis correlates with several proteins, including myelin basic protein (MBP). However, little is known about the adverse effects of exposure to propofol on MBP, particularly during embryonic development. Our goal was to use zebrafish to explore the effect of propofol on embryonic development, apoptosis and MBP expression. Zebrafish embryos were exposed to propofol at defined doses and stages from 6 to 48 h postfertilization by immersion. The survival rate, hatchability, aberration rate, cell apoptosis and gene expression were analyzed at defined stages. Analysis revealed that doses of 1, 2 and 3 µg ml(-1) propofol were reasonable anesthetic concentrations for zebrafish embryos. These doses of propofol caused a significant decrease in hatchability and an increase in aberration rate. Moreover, 6 days postfertilization (dpf) larvae are anesthetized by immersion into water containing 1, 2 or 3 µg ml(-1) of propofol. The number of apoptotic cells in the head of propofol-treated 36 h postfertilization embryos were significantly increased, and the expression of caspases-3, -8 and -9 were upregulated. Apoptosis was also induced in the brain of 3 dpf larvae exposed to propofol. However, propofol caused a decrease in mbp gene and protein (dose-dependent) expression levels in the central nervous system of 3 dpf zebrafish. These data show that embryonic exposure to propofol is neurotoxic, causing increased apoptosis and decreased MBP expression. We believe zebrafish can be used as a novel model to explore the mechanisms of propofol neurotoxicity. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 06/2015; 35(12). DOI:10.1002/jat.3183 · 2.98 Impact Factor
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    • "During administration period, pups were kept warm at body temperature by placing heating pad under and heating lamps above the cages. Previous experiments of higher dosages and longer series of injections of propofol confirmed that animals do not show respiratory, metabolic, circulatory, or glycemic alterations (Briner et al., 2011; Yu et al., 2013; Gao et al., 2014). Pups were closely monitored during the sedated state observing their appearance and respiration. "
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    ABSTRACT: Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner.
    Biomolecules and Therapeutics 05/2015; 23(3):251-260. DOI:10.4062/biomolther.2014.120 · 1.73 Impact Factor
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    • "Previous studies have shown that anesthetic-induced toxicity and synaptic effects in hippocampal and cortical cultures or slices depend on the neurodevelopmental stage. In early development prior to spine formation, exposure to anesthetics reduces subsequent dendritic spine and filopodial density [8]–[10]. In contrast, during peak synaptogenesis, anesthetic exposure increases dendritic spine density [11], [12]. "
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    ABSTRACT: General anesthetics produce a reversible coma-like state through modulation of excitatory and inhibitory synaptic transmission. Recent evidence suggests that anesthetic exposure can also lead to sustained cognitive dysfunction. However, the subcellular effects of anesthetics on the structure of established synapses are not known. We investigated effects of the widely used volatile anesthetic isoflurane on the structural stability of hippocampal dendritic spines, a postsynaptic structure critical to excitatory synaptic transmission in learning and memory. Exposure to clinical concentrations of isoflurane induced rapid and non-uniform shrinkage and loss of dendritic spines in mature cultured rat hippocampal neurons. Spine shrinkage was associated with a reduction in spine F-actin concentration. Spine loss was prevented by either jasplakinolide or cytochalasin D, drugs that prevent F-actin disassembly. Isoflurane-induced spine shrinkage and loss were reversible upon isoflurane elimination. Thus, isoflurane destabilizes spine F-actin, resulting in changes to dendritic spine morphology and number. These findings support an actin-based mechanism for isoflurane-induced alterations of synaptic structure in the hippocampus. These reversible alterations in dendritic spine structure have important implications for acute anesthetic effects on excitatory synaptic transmission and synaptic stability in the hippocampus, a locus for anesthetic-induced amnesia, and have important implications for anesthetic effects on synaptic plasticity.
    PLoS ONE 07/2014; 9(7):e102978. DOI:10.1371/journal.pone.0102978 · 3.23 Impact Factor
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