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; DOI:10.1002/jat.3183 · 2.98 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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    • "However, both anesthetics have no significant effects on the number of dendritic spines, and the changes in filopodial dynamics seem transient and not long-lasting [109]. Similar to the changes observed in dendritic spines and filopodia-like structures during blocked synaptic transmission [110], these findings suggest that the effects of anesthetic exposure on synaptic connectivity in the brain may depend on developmental stage level [111]. These studies also show that the fate of synaptogenesis depends on the dose of anesthetics. "
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    ABSTRACT: Compelling evidence has shown that exposure to anesthetics used in the clinic can cause neurodegeneration in the mammalian developing brain, but the basis of this is not clear. Neurotoxicity induced by exposure to anesthestics in early life involves neuroapoptosis and impairment of neurodevelopmental processes such as neurogenesis, synaptogenesis and immature glial development. These effects may subsequently contribute to behavior abnormalities in later life. In this paper, we reviewed the possible mechanisms of anesthetic-induced neurotoxicity based on new in vitro and in vivo findings. Also, we discussed ways to protect against anesthetic-induced neurotoxicity and their implications for exploring cellular and molecular mechanisms of neuroprotection. These findings help in improving our understanding of developmental neurotoxicology and in avoiding adverse neurological outcomes in anesthesia practice.
    International Journal of Molecular Sciences 12/2012; 13(6):6772-99. DOI:10.3390/ijms13066772 · 2.86 Impact Factor
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