In contrast to rare copy number variants (CNVs) causing classical syndromes such as Smith-Magenis syndrome and Williams syndrome, recent studies have identified a class of rare CNVs associated with the risk of developing a wide variety of neurodevelopmental and neuropsychiatric features. Individuals affected by these variants often have carrier parents who are apparently unaffected or manifest only subclinical neuropsychiatric features. This makes genetic diagnosis, counseling and management of individuals affected by such CNVs difficult. Several identified CNVs of this category, including 16p11.2 deletion, 1q21.1 deletion, 15q13.3 deletion and 16p12.1 deletion, collectively account for about 20 percent of individuals with neurodevelopmental disorders. Although these CNVs confer higher risk for a disorder, alone they are not sufficient for the manifestation of the disorder. It is therefore essential to consider additional genetic factors that may account for the observed variability in manifestation of these disorders.

A large number of autism risk genes encode proteins that play critical roles in regulating the formation, maturation and function of synaptic connections in the brain, yet the underlying molecular mechanisms of autism are poorly understood. Synaptic connections in the brain consist of the presynaptic axon, the postsynaptic dendrite and the ensheathing astrocytic process. Astrocytes are morphologically complex, non-neuronal cells that play critical roles in synapse assembly, maturation and function.

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental syndromes characterized by repetitive behaviors and deficits in the core domains of language development and social interactions. Although the clinical criteria used to define ASDs are entirely behavioral, a wealth of research suggests that mechanisms underlying sensory processing and sensorimotor coupling are altered in individuals with ASDs, and that these differences significantly contribute to ASD pathology. However, the neural basis for these sensory and sensorimotor phenotypes are not completely understood.

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.