In light of the preceding findings

In light of the preceding findings, the study by Darville and colleagues () is timely. They explored the therapeutic potential of more than 200 pharmacological agents, using neurons differentiated from iPS cells derived from ASD individuals heterozygous for null mutations. Darville et al. applied a comprehensive step-wise approach to identify potentially effective compounds. Using a qPCR-based high throughput screening (HTS) method, they quantified the relative expression of after treating day-14 neurons with the test compounds, some of which were FDA-approved psychotropic drugs. The authors found six compounds that increased mRNA in a concentration-dependent manner, of which three were validated at the protein level: lithium, valproic MK-1775 cost (VPA), and fluoxetine. They performed a quantitative immunostaining analysis of synapses using pre-synaptic and post-synaptic neuronal markers. Only neurons treated with lithium and VPA showed evidence of staining for all the synaptic markers - indicative of increased activity. Recording spontaneous calcium oscillations (SCO) in the neurons at a later stage revealed that only lithium and VPA increased their intensity and frequency. Transcriptome analysis demonstrated that, compared to VPA, lithium targets a narrower range of neuronal and synaptic genes, which perhaps could translate into a more specific and safer treatment. To identify molecular pathways that lithium and VPA possibly share in their effect on expression, the authors hypothesized that Glycogen Synthase Kinase 3 (GSK3) and/or class I Histone Deacetylase (HDAC) could be the possible common targets. Treating the iPS cell-derived neurons with two agents, CHIR99021 (a selective GSK3 inhibitor) and Trichostatin A (a selective HDAC inhibitor) revealed that only the latter agent increased mRNA. Similarly, a pathway enrichment analysis on genes regulated by lithium and VPA showed that histone modifications, but not GSK3 , is the more likely mechanism shared by these two drugs in the upregulation of .
The index event of birth has always been viewed as the most challenging physiologic adaptation of our lives. With the emergence of microbiome science, we have appreciated yet another critical transition that occurs at birth: the fetus exits the sterile (or at least low in microbial biomass ()) environment of the womb to enter the outer world ecosystem with abundant microorganisms. This route of entry to the microbial world, or mode of delivery, can determine which of the mother\'s microbes have the first shot at founding colonies within the baby\'s body. Vaginal birth offers a prolonged exposure to vaginal and intestinal microbiota, whereas Caesarian section (C-section) directly exposes the fetus to skin and environmental microbes (). As the seeds of the developing infantile microbiome are planted at birth, the well-established downstream associations of C-section with childhood respiratory illness, such as asthma and respiratory infections (), may in fact reflect the effects of C-section on microbiota. With extensive evidence linking specific profiles of the respiratory microbiome of children with subsequent development of respiratory illnesses (), in this issue of examine a logically emerging hypothesis: does C-section impact the evolution of the upper respiratory microbiome? In this well-designed birth cohort study, the investigators prospectively followed 102 neonates born either vaginally or by C-section and repeatedly sampled their nasopharyngeal microbiome at regular intervals up to six months of age. Immediately after birth, the nasopharynx of babies was coated by a low biomass bacterial community of mixed origin, with species of presumed fecal and vaginal origin being more common in vaginally-delivered neonates. Following an outgrowth of by 24h after birth, neonates developed individual succession patterns of community composition and transitioned through four major bacterial clusters. Importantly, mode of delivery was not exclusively associated with any specific clusters, but instead with the rate by which children transitioned through different clusters to reach more stable community profiles. Thus, children born by C-section stayed longer in a -dominated cluster whereas vaginally-delivered children switched earlier to (more mature) profiles with , and , bacteria previously shown to be protective from respiratory illnesses ().