Ketamine Modulates Zic5 Expression via the Notch Signaling Pathway in Neural Crest Induction

Abstract

Ketamine is a potent dissociative anesthetic and the most commonly used illicit drug. Many addicts are women at childbearing age. Although ketamine has been extensively studied as a clinical anesthetic, its effects on embryonic development are poorly understood. Here, we applied the Xenopus model to study the effects of ketamine on development. We found that exposure to ketamine from pre-gastrulation (stage 7) to early neural plate (stage 13.5) resulted in disruption of neural crest (NC) derivatives. Ketamine exposure did not affect mesoderm development as indicated by the normal expression of Chordin, Xbra, Wnt8, and Fgf8. However, ketamine treatment significantly inhibited Zic5 and Slug expression at early neural plate stage. Overexpression of Zic5 rescued ketamine-induced Slug inhibition, suggesting the blockage of NC induction was mediated by Zic5. Furthermore, we found Notch signaling was altered by ketamine. Ketamine inhibited the expression of Notch targeted genes including Hes5.2a, Hes5.2b, and ESR1 and ketamine-treated embryos exhibited Notch-deficient somite phenotypes. A 15 bp core binding element upstream of Zic5 was induced by Notch signaling and caused transcriptional activation. These results demonstrated that Zic5 works as a downstream target gene of Notch signaling in Xenopus NC induction. Our study provides a novel teratogenic mechanism whereby ketamine disrupts NC induction via targeting a Notch-Zic5 signaling pathway.

The association of ZIC5 gene rs965623242 polymorphism with neural tube defects

“…Recently, the ZIC5 gene has been shown to play a role in induction along with Wnt downstream signals and Notch upstream signals [38]. Prevention of neuronal closure (NC) induction occurs through early embryonic exposure to ketamine, which inhibits notch-targeted gene expression, including the ZIC5 gene [40]. Based on the effects of the ZIC5 gene on cell proliferation, the AA genotype may cause low expression levels, and NC problems by producing a negative effect on the cell division along the edges of the neural plate.…”

Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis

“…This notion is further supported by a recent finding that ketamine exerts its antidepressant effects via weakening of ubiquitin ligase activity and subsequently enhanced mTOR signaling [ 72 ]. However, ketamine was also found to increase the ubiquitination of Notch to disrupt downstream targets of the Notch signaling pathway in the Xenopus model of neurodevelopment [ 73 ], surfacing a potential controversy in the ubiquitination-mediated mechanism of ketamine. Thus, these findings demand additional research to clarify the biological impact of ketamine on ubiquitin-mediated proteolysis in vivo .…”

Neurocritical Care of the Pregnant Patient

“…Despite absence of trial data, expert consensus recommends consideration of ultra-mild hypothermia (36°C) in post-maternal CA to avoid further impact on the coagulopathy of pregnancy. The same protocol should be used as for non-pregnant patients [ 80 , 82 , IIb]. Typical fetal effects of hypothermia are decreased fetal heart rate and variability.…”