Supplement: Proceedings of the Sixth PANDA Symposium on “Anesthesia and Neurodevelopment in Children”Early Developmental Exposure to Repetitive Long Duration of Midazolam Sedation Causes Behavioral and Synaptic Alterations in a Rodent Model of NeurodevelopmentXu, Jing MD*,†; Mathena, Reilley Paige BSc†; Singh, Shreya BSc†; Kim, Jieun BSc†; Long, Jane J. BSc†; Li, Qun MD†; Junn, Sue BSc†; Blaize, Ebony BSc†; Mintz, Cyrus David MD, PhD†Author Information *Department of Anesthesiology, The Second Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an, Shaanxi, China †Department of Anesthesiology and Critical Care Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD J.X. and R.P.M.: contributed to behavior tests. J.K., J.J.L., and S.J.: contributed to IHC. J.X.: contributed to imaging. E.B. and S.S.: contributed to image quantification. J.X.: contributed to data analysis. This study is supported in part by 1R01GM120519 (CDM). The authors have no funding or conflicts of interest to disclose. Address correspondence to: Cyrus David Mintz, MD, PhD, Department of Anesthesiology, Ross Bldg. 370, 720 Rutland Ave, Johns Hopkins School of Medicine, Baltimore, MD 21205 (e-mail: email@example.com). Journal of Neurosurgical Anesthesiology: January 2019 - Volume 31 - Issue 1 - p 151-162 doi: 10.1097/ANA.0000000000000541 Buy Metrics Abstract There is a large body of preclinical literature suggesting that exposure to general anesthetic agents during early life may have harmful effects on brain development. Patients in intensive care settings are often treated for prolonged periods with sedative medications, many of which have mechanisms of action that are similar to general anesthetics. Using in vivo studies of the mouse hippocampus and an in vitro rat cortical neuron model we asked whether there is evidence that repeated, long duration exposure to midazolam, a commonly used sedative in pediatric intensive care practice, has the potential to cause lasting harm to the developing brain. We found that mice that underwent midazolam sedation in early postnatal life exhibited deficits in the performance on Y-maze and fear-conditioning testing at young adult ages. Labeling with a nucleoside analog revealed a reduction in the rate of adult neurogenesis in the hippocampal dentate gyrus, a brain region that has been shown to be vulnerable to developmental anesthetic neurotoxicity. In addition, using immunohistochemistry for synaptic markers we found that the number of presynaptic terminals in the dentate gyrus was reduced, while the number of excitatory postsynaptic terminals was increased. These findings were replicated in a midazolam sedation exposure model in neurons in culture. We conclude that repeated, long duration exposure to midazolam during early development has the potential to result in persistent alterations in the structure and function of the brain. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.