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.

BACKGROUND Nutrition is important for the fetal developmental programming. Nutritional deficiency in early life could increase the susceptibility to many aging-related disorders including cognitive decline. OBJECTIVE Our study aims to investigate the effect of early famine exposure on aging-associated cognitive function. METHODS We recruited 6790 subjects born between 1956 to 1964 during which the Great Chinese Famine occurred (1959-1961). Cognitive function of these subjects were evaluated using the Mini-Mental State Examination (MMSE), the Activities of Daily Living scale (ADL), the Instrumental Activities of Daily Living scale (IADL) and the Clinical Dementia Rating (CDR). RESULTS Our study identified that early exposure to the famine significantly increased the risk of cognitive impairments in later life, leading to higher prevalence of Mild Cognitive Impairment (MCI) and dementia. We also found the sex and rural-urban differences in this malnutrition-induced effect. Illiteracy, history of stroke or diabetes mellitus are great risk factors to facilitate the cognitive decline. CONCLUSION These findings demonstrate that exposure to famine during early life including prenatal period and early childhood facilitates aging-associated cognitive deficits.

Apolipoprotein E (ApoE) plays a vital role in cholesterol metabolism and its allele polymorphisms have been associated with several diseases including Alzheimer's disease (AD). There are few systematic studies on ApoE polymorphism and its association with AD in Chinese population. To examine this issue, participants included 4251 subjects and 404 AD patients with 390 healthy elderly residing in Chongqing city were genotyped. The results showed that the ε3 allele presented the highest frequency (82%), followed by ε4 (6.25%) and ε2 (11.75%) in general population. ε3/ε3 genotype carriers are the most common ones (64.19%) and the ε4/ε4 had the lowest frequency (0.59%). The frequency of ApoEε4 allele frequency in AD (15.35%) was significantly higher than control (10.00%). Those carriers of two ε4 allele have five time higher risk to develop AD. Our study demonstrate that ApoEε4 allele is a risk factor of AD for Chinese population.

Alcohol is detrimental to early development. Fetal alcohol spectrum disorders (FASD) due to maternal alcohol abuse results in a series of developmental abnormalities including cranial facial dysmorphology, ocular anomalies, congenital heart defects, microcephaly and intellectual disabilities. Previous studies have been shown that ethanol exposure causes neural crest (NC) apoptosis and perturbation of neural crest migration. However, the underlying mechanism remains elusive. In this report we investigated the fetal effect of alcohol on the process of neural crest development in the Xenopus leavis.