Ketamine exposure in early development impairs specification of the primary germ cell layers

Abstract

Preclinical and clinical evidence implicates N-methyl-D-aspartate receptor (NMDAr) signaling in early embryological development. However, the role of NMDAr signaling in early development has not been well studied. Here, we use a mouse embryonic stem cell model to perform a step-wise exploration of the effects of NMDAr signaling on early cell fate specification. We found that antagonism of the NMDAr impaired specification into the neuroectodermal and mesoendodermal cell lineages, with little or no effect on specification of the extraembryonic endoderm cell lineage. Consistent with these findings, exogenous NMDA promoted neuroectodermal differentiation. Finally, NMDAr antagonism modified expression of several key targets of TGF-β superfamily signaling, suggesting a mechanism for these findings. In summary, this study shows that NMDAr antagonism interferes with the normal developmental pathways of embryogenesis, and suggests that interference is most pronounced prior to neuroectodermal and mesoendodermal cell fate specification.

Neurotransmitter signaling pathways required for normal development inXenopus laevisembryos: a pharmacological survey screen

“…In addition, ketamine downregulated Otx2, which is necessary for RPE development (Beby & Lamonerie, ; Akeju et al. ). Like ketamine, ethanol also works primarily through NMDA receptors (Silvestre de Ferron et al.…”

“…In mouse embryonic stem cell embryoid bodies, norketamine's parent compound ketamine impaired differentiation of the neuroectoderm, from which neural crest and retina are derived. In addition, ketamine downregulated Otx2, which is necessary for RPE development (Beby & Lamonerie, 2013;Akeju et al 2014). Like ketamine, ethanol also works primarily through NMDA receptors (Silvestre de Ferron et al 2015), and fetal alcohol syndrome is associated with craniofacial and ocular abnormalities in humans.…”

Effects of prolonged anesthesia with dexmedetomidine, fentanyl, or remifentanil on the self-renewal of mouse embryonic stem cells

“…Furthermore, retinoblastoma (RB) family proteins bind and repress the E2F family of transcription factor to restrict the G1/S transition (Conklin et al, 2012). mESCs themselves also express functional receptors associated with anesthetics such as GABA, NMDA, opioid, and adrenergic receptors (Kim et al, 2006;Andäng et al, 2008;Kim et al, 2008;Schwirtlich et al, 2010;Akeju et al, 2014). Therefore, while studies have shown that the proliferation of ESCs was crucial to maintain the stemness of ESCs, few researchers have been concerned with the question of how anesthetics influence the self-renewal of ESCs.…”

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

“…At this early point in the pregnancy, most women are not aware that they are pregnant until the next regular menstrual cycle. While ketamine exposure has been shown to affect cell survival ( Brambrink et al, 2012 ; Bai et al, 2013 ), germ layer specification ( Akeju et al, 2014 ), neurogenesis ( Cuevas et al, 2013 ; Kanungo et al, 2013 ; Dong et al, 2014 ), cardiac morphogenesis ( Guo et al, 2016 ), and craniofacial and trunk genesis ( Felix et al, 2017 ), the effect of ketamine on early embryonic development is poorly understood.…”

“…The impact of illicit ketamine use on embryonic development during pregnancy could be detrimental. Previous studies using zebrafish, Xenopus and rat models showed its disruptive effects on motor-neuron development ( Kanungo et al, 2013 ), primary germ cell layers specification ( Akeju et al, 2014 ), cardiac morphogenesis ( Guo et al, 2016 ), neural genesis and survival ( Dong and Anand, 2013 ; Dong et al, 2014 ). More recently, a report suggested craniofacial and trunk phenotypes upon embryonic ketamine exposure in Zebrafish ( Felix et al, 2017 ).…”