Somatic mosaicism, or the emergence of variations in the sequence or structure of the genome of somatic cells, has been detected in both healthy individuals and individuals with various diseases, particularly cancer. It has been suggested that somatic variations play a major role in driving neuronal diversity and genome evolution. However, the extent to which mosaicism occurs in normal development, and its significance in brain disorders, has only recently begun to be investigated.

Components of the mammalian target of rapamycin (mTOR) signaling pathway are key players in the pathogenesis of autism spectrum disorder (ASD). The mTOR pathway regulates protein homeostasis by promoting protein synthesis and inhibiting autophagy, a lysosomal degradation process that maintains protein quality control by breaking down cellular proteins and organelles to generate amino acids. Guomei Tang, David Sulzer and their colleagues at Columbia University Medical Center recently analyzed postmortem brain samples from individuals with ASD and discovered that, in response to hyperactive mTOR, autophagy was impaired in excitatory neurons. In animal models, autophagy deficiency causes ASD-like synapse pathology and social behaviors.

Fragile X syndrome is the most common heritable form of intellectual disabilities and a leading genetic cause of autism, caused by mutation of the gene encoding FMRP. Researchers have not found an effective treatment for the cognitive and social interaction deficits associated with fragile X. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, proliferation, survival, translation and the actin cytoskeleton. mTOR is a kinase that integrates external cues and forms two distinct complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2), which have distinct functions and downstream targets. Whereas mTORC1 is a central regulator of cap-dependent translation, mTORC2 is a pivotal regulator of the actin cytoskeleton, spine structure and memory. Dysregulation of mTORC1 in fragile X syndrome is well established, but a role for mTORC2 is still unclear.

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.

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.