Several key barriers exist to unraveling the mechanistic etiologies of autism spectrum disorder (ASD). There is increasing appreciation that ASD pathology, while genetically heterogeneous, may result from disruptions to common multicellular interactions that impact cortical circuitry and alter excitatory/inhibitory (E/I) balance. Duplication or triplication of maternally inherited 15q11-13, the chromosomal location where UBE3A resides, is one of the most common genetic variants linked to ASD. UBE3A is an E6 ubiquitin ligase that controls the levels of key synaptic proteins, and UBE3A activity has been shown to control E/I balance in the cerebral cortex of mice.

Genetic risks for autism are diverse and encompass mutations and copy number variations in hundreds of genes. However, autism is diagnosed through the evaluation of a shared set of symptoms that include social interaction deficits and repetitive or restrictive behaviors.

Anthony Wynshaw-Boris and his colleagues are investigating the hypothesis that a subset of individuals with autism spectrum disorders (ASD) (approximately 25-30 percent) display early brain overgrowth. His lab has recently produced two relevant models that recapitulate important aspects of early brain overgrowth in ASD. First, the team produced a mouse model deficient for DVL1 and DVL3 (Dvl1/3 +/– mutants). These mice display adult social behavior abnormalities associated with transient embryonic brain enlargement during the time of deep-layer cortical formation. Second, they generated human induced pluripotent stem cell (iPSC) models by reprogramming fibroblasts obtained from individuals with ASD who had early head overgrowth and unaffected control individuals with normal head circumference. Neuronal progenitor cells (NPCs) derived from ASD iPSC lines displayed enhanced proliferation compared to control NPCs. In both the Dvl 1/3 mutant mouse model and the human iPSCs, the observed phenotypes were caused by down-regulation of beta-catenin activity and its direct target BRN2. This remarkable conservation of beta-catenin and BRN2 signaling disruption in different models of ASD suggests that multiple variants contributing to ASD may converge on common pathways.

The gene encoding the transcription factor FOXP1 is strongly implicated in the etiology of individuals with autism spectrum disorder (ASD) and of those with intellectual disability. FOXP1 is among the 40 highest-ranked candidate ASD risk genes (according to SFARI Gene). Brain-wide deletion of FOXP1 in mice results in altered behaviors relevant to ASD.

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.