One of the most critical challenges in the identification of new medications to treat autism spectrum disorders (ASDs) is our limited understanding of the biological mechanisms underlying these disorders. In recent years, there have been considerable advances in the genetics of ASD, with a resulting rapidly accumulating pool of reliable ASD risk genes. Currently, we need systems that will allow us to progress from gene discovery to the illumination of relevant biological pathways and novel therapeutics.

The brain is an exquisitely complex network, and the precise development of neuronal connections into the appropriate circuitry is crucial in determining brain function. Malformation of these connections during prenatal and early postnatal development can lead to neurological deficits, including intellectual disability, autism and schizophrenia. While inappropriate circuit formation has been suggested to be a critical deficit in autism, precisely whether and how various autism-related gene mutations lead to such defects remains unclear.

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.

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.

Dysregulation of the normal immune response appears to underlie the development of a wide variety of neurodegenerative diseases, including autism spectrum disorders (ASDs). Animal models of ASD have demonstrated that maternal infection or abnormal immune signaling contribute to the development of autism-like disorders. Together, these findings suggest that immune response genes play an important role in the generation of ASDs.

All cells, including neurons, possess mechanisms to coordinate protein synthesis with protein degradation to maintain amino acid and protein levels within the appropriate range. Even a subtle imbalance between these processes can disrupt normal neuronal morphology and functions.

Autism arises in early childhood, during a period of intense learning when many of the brain’s connections are modified by experience. Several autism-associated proteins also play important roles in memory formation.

The generation of all-or-none action potentials is critical for proper brain function. At the heart of action potential generation are voltage-gated sodium channels, which underlie the rising, or depolarizing, phase of the action potential. Twelve different mutations in the SCN2A gene, which encodes the neuronal sodium channel NaV1.2, have been identified in two large autism genetic studies.

Abnormal patterns of head and brain growth have been reported in a subset of individuals with autism. A heterogeneous collection of genetic risk factors for autism and micro- and macrocephaly have been identified, including mutations in genes acting in the PI3K-AKT-mTOR (e.g., PTEN) and Wnt-beta-catenin (e.g., CTNNB1, CHD8 and TCF4) signaling pathways.