The effects of prenatal exposure to drugs on brain development are complex and are modulated by the timing, dose, and route of drug exposure. It is difficult to assess these effects in clinical cohorts, which are beset with multiple exposures and difficulties in documenting use patterns. This can lead to misinterpretation of research findings by the general public, the media and policy makers, who may mistakenly assume that the legal or illegal status of a drug correlates with its biological impact on fetal brain development and long-term clinical outcomes. It is important to close the gap between what science tells us about the impact of prenatal drug exposure on the fetus and the mother, and what we do programmatically with regard to at-risk populations.

Inositol (1,4,5)triphosphate (InsP3) and tetrakisphosphate (InsP4) have been observed in a variety of cell types and have been proposed to play roles in the receptor-mediated rise in intracellular Ca2+ (refs 2, 3). Recently, they have been shown to act synergistically in the activation of a Ca2+-dependent K+ channel in lacrimal acinar cells. InsP3 is the product of phospholipase C (PLC) action on phosphatidylinositol 4,5-bisphosphate (PtdInsP2) whereas InsP4 is believed to arise from phosphorylation of InsP3 by a cytosolic kinase. Although sought as a source for InsP4, PtdInsP3 has not been identified in any specific cell type. There were early reports of InsP4-containing phospholipids in crude extract from bovine brain, but this finding was later withdrawn. Recently, however, a membrane-bound enzyme (Type 1 PI kinase) which adds phosphate onto the 3 position of inositol phospholipids has been identified and the phosphatidylinositol-3-phosphate (PtdIns(3)P) product characterized. This suggests that several forms of phosphoinositides may exist and could be precursors for some of the variety of soluble inositol phosphate products which have been reported in recent years. Here we report the appearance of another novel phosphoinositide containing four phosphates, phosphatidylinositol trisphosphate (PtdInsP3) which we find only in activated but not in unstimulated neutrophils from human donors.

Chromodomain helicase DNA-binding protein 8 (CHD8) was identified as a leading autism spectrum disorder (ASD) candidate gene by whole-exome sequencing and subsequent targeted-sequencing studies. De novo loss-of-function mutations were identified in 12 individuals with ASD and zero controls, accounting for a highly significant association. Small interfering RNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA sequencing revealed that CHD8 insufficiency results in altered expression of 1715  genes, including both protein-coding and noncoding RNAs. Among the 10 most changed transcripts, 4 (40%) were noncoding RNAs. The transcriptional changes among protein-coding genes involved a highly interconnected network of genes that are enriched in neuronal development and in previously identified ASD candidate genes. These results suggest that CHD8 insufficiency may be a central hub in neuronal development and ASD risk.