GABA is the key inhibitory neurotransmitter of the mature brain, and most synaptic inhibition is mediated by GABAA receptors. These receptors are chloride-permeable ion channels, which means that the strength of inhibition depends on the Cl– gradient across the membrane. Dysregulation of Cl– homeostasis has emerged as a key mechanism underlying several brain disorders, including autism spectrum disorders (ASDs). Blockade of the Cl– importer NKCC1, with the diuretic bumetanide, restores normal behavioral phenotypes in experimental models of ASD, validating the restoration of Cl– homeostasis as a therapeutic strategy for ASDs.

The genetic heterogeneity of autism spectrum disorders (ASDs) has hindered the development of targeted therapies. Recently, genomic studies have revealed that many gene products that confer ASD risk converge on a surprisingly limited number of biological networks, including those controlling synaptic function. Such findings are consistent with the synaptic and behavioral hyperexcitability observed in individuals with ASD and mouse models of ASDs with impaired GABAergic inhibition. These studies suggest that targeting GABA neurotransmission could be an effective ‘network strategy’ of treatment applicable to ASDs of multiple etiologies. However, current GABA agonists are often ineffective and have considerable side effects. Novel drugs that safely restore GABA inhibition are therefore an urgent and unmet clinical need.

Both genetic and environmental factors contribute to the development of autism spectrum disorder (ASD). Maternal inflammation during pregnancy is known to increase the risk of ASD and other neuropsychiatric disorders in offspring, but the mechanism by which this occurs is still poorly understood. For example, it is currently unknown whether the gut microbiota composition in the mother during pregnancy influences the inflammation associated with ASD or if microbe-regulated immune responses are translated into effectors of ASD phenotypes in the offspring.

One hallmark of several autism spectrum disorders (ASDs) is altered protein synthesis in the brain, which results in synaptic dysfunction and disease pathology. Genetic variations in PTEN, TSC1, TSC2, FMR1, SHANK3 and NLGN3, and microdeletions at 16p11.2 have all been linked to ASDs, and mouse models of these mutations exhibit alterations in a form of synaptic plasticity called metabotropic glutamate receptor-induced long-term depression (mGluR-LTD). Many studies support a role for mGluR-LTD in learning, with alterations in mGluR-LTD linked to a variety of neurological disease states, including ASDs. These studies have also demonstrated that the proper functioning of mGluR-LTD relies on rapid synthesis of proteins, leading to the suggestion that aberrations in mRNA translation may contribute to disease pathology. However, it remains unclear what particular mRNAs are involved in this process.

Technological advances in whole-genome sequencing (WGS) to study complex genetic disorders have outpaced innovations in the analysis of large genetic datasets. An ever-increasing amount of genetic data is being acquired, at a higher resolution, from patient populations numbering in the thousands. While this has led to the identification of many genes and genetic variants associated with increased risk for disorders, such as autism spectrum disorder (ASD), novel biological insight from these datasets has lagged behind.

Genetics plays a central role in autism spectrum disorder (ASD), yet much remains unknown about how DNA sequence variation predisposes individuals to ASD. Rare mutations have emerged as critical in ASD, and there is great hope that whole-genome sequencing will reveal many more causal mutations and lead to a better understanding of genetics and pathogenesis in ASD. This presumes that we will be able to identify which DNA mutations predispose individuals to ASD against the background of the millions of benign or unrelated DNA mutations present in every human genome. For mutations that disrupt proteins, such causal relationships have been successfully demonstrated, leading to significant new insights into the etiology of ASD. However, the majority of the human genome does not code for proteins, and predicting which mutations are pathogenic in noncoding regions is much more challenging. Enhancers — regulatory DNA sequences within our genomes that control when genes are activated — have emerged as critically important to human health and development. It is likely that noncoding mutations that disrupt enhancers also contribute to the pathogenesis of ASD.

Amniotic fluid (AF) and cerebrospinal fluid (CSF) are routinely sampled for biomarkers of diseases, including autism spectrum disorder (ASD). The cerebral cortex, which governs higher cognitive functions, initially develops from neural stem cells that interface with CSF-filled ventricles. Surprisingly little is known about how fluid-borne signals are distributed across the developing brain, or about the mechanisms by which changes in fluid composition actively instruct brain development.

Autism spectrum disorders (ASD) are frequently associated with immune dysregulation. Peripheral immune responses and microglial function have been the major focus in the field. However, recent studies have suggested that neurons are also able to use their own innate immune receptors, including toll-like receptors (TLRs), to detect the danger signals derived from both endogenous cells and pathogens.