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Hippocampal SIRT1-Mediated Synaptic Plasticity and Glutamatergic Neuronal Excitability Are Involved in Prolonged Cognitive Dysfunction of Neonatal Rats Exposed to Propofol

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Abstract

Neonates who receive repeated or prolonged general anesthesia before the age of 4 are at a significantly higher risk of developing cognitive dysfunction later in life. In this study, we investigated the effects of repeated neonatal propofol exposure on hippocampal synaptic plasticity, neuronal excitability, and cognitive function. Adeno-associated SIRT1 virus with CaMKIIɑ promotor and a viral vector carrying the photosensitive gene ChR2 with the CaMKIIɑ promotor, as well as their control vectors, were stereotaxically injected into the hippocampal CA1 region of postnatal day 5 (PND-5) rats. PND-7 rats were given intraperitoneal injection of 60 mg/kg propofol or fat emulsion for three consecutive days. Western blotting, Golgi staining, and double immunofluorescence staining were used to evaluate the SIRT1 expression, synaptic plasticity, and the excitability of neurons in the hippocampal CA1 region. The Morris water maze (MWM) test was conducted on PND-30 to assess the learning and memory abilities of rats. Repeated neonatal propofol exposure reduced SIRT1 expression, suppressed synaptic plasticity, decreased glutamatergic neuron excitability in the hippocampus, and damaged learning and memory abilities. Overexpression of SIRT1 attenuated propofol-induced cognitive dysfunction, excitation-inhibition imbalance, and synaptic plasticity damage. After optogenetic stimulation of glutamatergic neurons in the hippocampal CA1 region, the learning and memory abilities of rats exposed to propofol were improved on PND-30. Our findings demonstrate that SIRT1 plays an important role in cognitive dysfunction induced by repeated neonatal propofol exposure by suppressing synaptic plasticity and neuronal excitability.

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Funding

This work is supported by the National Natural Science Foundation of China (81971051, 82171191) and the Natural Science Foundation of Jiangsu Province (BK20191464).

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  1. Lin-Hui Ma, Jie Wan and Jing Yan contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of China

    Lin-Hui Ma, Jie Wan, Jing Yan, Ning Wang, Yan-Ping Liu, Hai-Bi Wang & Yu-Qing Wu

  2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, People’s Republic of China

    Cheng-Hua Zhou

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  1. Lin-Hui Ma
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Contributions

As the corresponding author, Yu-Qing Wu conceived the study, completed its design and coordination, and secured funding for the project. Under the guidance and supervision of Yu-Qing Wu and Cheng-Hua Zhou, Lin-Hui Ma performed the neonatal propofol anesthesia, sample preparation, Golgi-Cox staining, double immunofluorescence staining, and the optogenetic stimulation. Jie Wan completed the data collection and statistical analysis. Jing Yan was responsible for the reproduction and feeding of rats. Ning Wang performed the Western blot experiment. Yan-Ping Liu and Hai-Bi Wang completed the Morris water maze test. All the authors have read and approved the final manuscript.

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Correspondence to Cheng-Hua Zhou or Yu-Qing Wu.

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Ma, LH., Wan, J., Yan, J. et al. Hippocampal SIRT1-Mediated Synaptic Plasticity and Glutamatergic Neuronal Excitability Are Involved in Prolonged Cognitive Dysfunction of Neonatal Rats Exposed to Propofol. Mol Neurobiol 59, 1938–1953 (2022). https://doi.org/10.1007/s12035-021-02684-4

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