Research into the developmental underpinnings of autism spectrum disorder (ASD) is hampered by a lack of techniques for describing neural development at the cellular and circuit levels. Ethan Scott and his colleagues plan to use zebrafish as a platform for anatomical and functional analyses of ASD etiology at the level of individual neurons and the circuits that they form. Zebrafish larvae are transparent, allowing neural development in the intact animal to be examined with a range of microscopic and optogenetic techniques.

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.

Single-nucleotide polymorphism genotyping and whole-exome and whole-genome sequencing studies have been key for the identification of genetic loci and mutations underlying autism spectrum disorder (ASD) susceptibility. Although none of the risk genes identified so far contribute to more than 1 percent of ASD cases, overall the search for ASD treatments can profoundly benefit from the study of rare and syndromic forms of ASDs.

Autism spectrum disorder (ASD) is diagnosed in an increasingly large proportion of the population. Changes in neurocircuitry resulting from alterations in genetic and epigenetic programming are thought to represent an underlying cause of ASD-related behavior, and alterations in the anatomical and electrophysiological properties of local neural circuits in mouse models of ASD have been described. Yet it remains unclear how changes in longer-range neural connectivity are affected in ASD. Bidirectional connections between the thalamus and cortex are one set of long-range projections that are critical for filtering, selecting and perceiving sensory stimuli and generating motor outputs. Interestingly, human imaging studies have implicated thalamocortical circuit dysfunction in ASD.

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.

Autism spectrum disorders (ASDs) comprise a heterogeneous set of neurodevelopmental and neuropsychiatric conditions that affect both social and nonsocial behavior. The laboratory mouse is currently the best mammalian system available for studying ‘genocopies’ of allelic variants found in humans. The use of such mouse genocopies in ASD research has come under criticism because of concerns that the behavioral assays used to phenotype these models are too crude and far removed from human behavior to be informative. These considerations have fueled a push for the use of non-human primate (NHP) models, such as the marmoset, in autism research. But such NHP models are expensive, laborious to generate, and present ethical problems. A complementary approach, therefore, is to develop more sensitive, objective and quantitative automated approaches to measuring ASD-related behavioral phenotypes in mice.

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.