A common feature of mouse models of autism spectrum disorders (ASDs) is an imbalance between excitation and inhibition within circuits of the central nervous system. This imbalance is thought to contribute to disrupted neural function in these disorders, but the ultimate cause of this imbalance remains unclear.

Copy number variants (CNVs) are the regions of the human genome that represent significant genetic risk factors for autism and other neurodevelopmental disorders. One such CNV located on chromosome 16, called 16p11.2, confers a high risk for developing autism and intellectual disability when deleted, and autism, schizophrenia, bipolar disorder and intellectual disability when duplicated. Even more intriguingly, 16p11.2 deletions are associated with increased head and brain size in the carriers (macrocephaly), whereas 16p11.2 duplications are associated with the decreased head and brain size (microcephaly). However, the exact mechanism by which this CNV influences brain size is unknown.

Half a century ago, the introduction of karyotyping transformed human genetics and clinical diagnostics by opening access to gross changes in chromosomes, revealing an entire class of previously undetectable genetic lesions. More recently, new technologies have refined our ability to search for genetic variants that cause disease. Yet in autism spectrum disorders (ASDs), a large proportion of genetic contribution still remains unexplained. Classes of chromosomal alterations that can cause loss-of-function mutations, namely balanced and complex structural variation (SVs), and copy number variants (CNVs), below the threshold of microarray —  collectively referred to as cryptic SVs — remain to be fully considered for their potential contribution to ASD.

Microglia — the brain’s resident immune cells — have many roles in normal brain development that neuroscience is just beginning to ascertain. It has long been known that microglia rapidly transform from a homeostatic to an ‘activated’ state following injury or disease and are recruited to sites of damage. A recent and increasing body of work now indicates that microglia also perform important roles in the normal development of the nervous system. For example, microglia sculpt neuronal circuits by removing under-utilized synapses. Microglia also appear to regulate synaptic maturation and plasticity and can impact behavior.

The core social impairments that characterize autism spectrum disorder (ASD) remain poorly understood. Improved understanding of ASD has been hindered by the inability to directly study brain tissue in ASD patients, and mice lack the complex social capabilities found in humans and other primates. These limitations have impeded the discovery of ASD biomarkers and the development of promising medications to treat social deficits seen in ASD.

Although 16p11.2 copy number variants (CNVs) make a significant contribution to the risk of autism spectrum disorder (ASD) and are becoming well described at the clinical level, the biological mechanisms underlying pathogenesis are not yet understood. MAPK3, MVP and KCTD13 — three of the genes in the 16p11.2 chromosomal region — are involved in RAS/MAPK signaling, a ubiquitous signaling pathway important for proliferation, differentiation and apoptosis across development. Interestingly, there is overlap between clinical and neuroimaging presentation in individuals with a 16p11.2 CNV and those with classic RASopathy syndromes, which are caused by dominant mutations activating RAS/MAPK signaling. There is also phenotypic overlap between 16p11.2 syndrome and RASopathy model organisms. Combined, these data suggest that alterations in RAS/MAPK signaling play an important role in the 16p11.2 CNV syndrome phenotype.

Autism can be thought of as a dysfunction in the interaction between cortical areas, particularly the top-down interactions that enable us to select features of our environment that are relevant for the task at hand and to suppress features that are task-irrelevant. Charles Gilbert and his colleagues at Rockefeller University propose a combination of behavioral and high-resolution imaging experiments to study the mechanisms of autism at the level of the circuitry of the cerebral cortex in animal models of autism.

Recent advances in sequencing analysis of individuals with autism have revealed a large number of genetic variations that are associated with autism. However, the causal role and mechanisms of these mutations are not known.

Mutations in the autism susceptibility candidate 2 gene (AUTS2) have long been linked with autism spectrum disorder (ASD) and several neurodevelopmental abnormalities. However, the molecular mechanisms by which AUTS2 functions in normal brain development and how it goes awry in ASD has remained elusive.