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Neonatal anesthesia impairs synapsin 1 and synaptotagmin 1, two key regulators of synaptic vesicle docking and fusion

Atluri, Navyaa,*; Ferrarese, Biancaa,d,*; Osuru, Hari P.a; Sica, Ryanb; Keller, Carolinec; Zuo, Zhiyia,†; Lunardi, Nadiaa,†

doi: 10.1097/WNR.0000000000001235
CELLULAR, MOLECULAR AND DEVELOPMENTAL NEUROSCIENCE
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Early exposure to anesthetics may interfere with synaptic development and lead to cognitive deficits. We previously demonstrated a decrease in vesicles docked at and within 100 nm from the presynaptic membrane in hippocampal nerve terminals of neonatal rats after anesthesia. Hence, we designed this study to assess the effects of neonatal anesthesia on synapsin 1 (Syn1) and synaptotagmin 1 (Syt1), two key regulators of vesicle docking and fusion. To test the link between changes in Syn1 and Syt1 and behavioral deficits observed after neonatal anesthesia, we also assessed retention memory and fear conditioning in adolescent rats after neonatal anesthesia. Pups received a combination of clinical anesthetics, then Syn1 and Syt1 mRNA and protein expression were determined at the peak (postnatal day 8, P8), part-way through (P12) and end of synaptogenesis (P24) in the CA1-subiculum by qPCR and western blotting. Anesthesia decreased Syn1 and Syt1 mRNA expression at P8 (P<0.01 and <0.001) and P12 (P=0.001 and 0.017), but not P24 (P=0.538 and 0.671), and impaired Syn1, p-Syn1, and Syt1 protein levels at P8 (P=0.038, 0.041, and 0.004, respectively), P12 (P<0.001, P=0.001, and P<0.0001), and P24 (P=0.025, 0.031, and 0.001). Anesthetic-challenged rats displayed deficient long-term retention memory (P=0.019) and hippocampus-dependent fear conditioning (P<0.001). These results suggest that anesthetics alter Syn1 and Syt1 during synapse assembly and maturation, raising the possibility that anesthetic interference with Syn1 and Syt1 could initiate changes in synaptic function that contribute to the cognitive deficits observed after neonatal anesthesia.

aDepartment of Anesthesiology, University of Virginia Health System

bSchool of Medicine

cUndergraduate Program, University of Virginia, Charlottesville, Virginia, USA

dDepartment of Anesthesiology, Universita’ degli Studi di Padova, Padova, Italy

* Navya Atluri and Bianca Ferrarese contributed equally to the writing of this article.

† Zhiyi Zuo and Nadia Lunardi contributed equally to the writing of this article.

Correspondence to Nadia Lunardi, MD, PhD, 21 Hospital Drive, Charlottesville, VA 22908, USA Tel: +1 434 243 9695; fax: + 1434 982 0019; e-mail: nl3f@virginia.edu

Received February 27, 2019

Accepted March 8, 2019

© 2019 Wolters Kluwer Health | Lippincott Williams & Wilkins