Over the past few years, studies have linked many genes to autism. With these discoveries comes the possibility of developing therapeutic approaches, but where to start? Alex Parker and his colleagues at the Centre Hospitalier de l’Universite de Montreal hope to use the worm C. elegans to find molecules that may be early drug development leads to help treat autism spectrum disorders.

Albert Basson and his colleagues at King’s College London plan to study the function of the CHD8 gene in brain development. CHD8, which encodes a protein that changes the structure of chromatin, has emerged as one of the most significant autism-associated genes. In vitro studies — studies conducted in an external environment — have suggested that CHD8 might function as a regulator of the developmentally important WNT signalling pathway, but whether this activity is relevant to CHD8 function during brain development is not known.

Studies since 2010 have identified a large number of genes that, when mutated, cause autism. One can group the products of these mutated genes into two categories: proteins located at the synapses, or functional connections between nerve cells, and proteins located in the cell nucleus.

KATNAL2 is a recently identified autism gene that is predicted to code for a microtubule-severing enzyme. However, researchers don’t know how this gene is involved in brain development or what cellular events in the developing brain go awry if it is mutated. Xiaobing Yuan and Peter Baas are studying whether KATNAL2 and other autism genes play an essential role in neuronal migration through the regulation of microtubule dynamics.

Accumulating evidence suggests that autism spectrum disorder symptoms arise from a disruption in the process of experience-dependent synaptic plasticity that normally occurs during critical periods of development. Critical periods are windows of time when appropriate sensory, motor and cognitive function are essential for the refinement and tuning up of brain circuits. Rett syndrome is recognized as one of the clearest genetic examples of autism, and is caused by mutations in the MeCP2 gene.

Fever or fever-associated illness in children with autism is reported to result in temporary relief of cognitive and behavioral symptoms. It remains unknown, however, which aspects of this phenomenon — such as temperature increase, immune activation, type of pathogen or type of autism — are important for this benefit to occur.

Genetic and neuroimaging studies provide strong evidence that the gene CNTNAP2 (also known as CASPR2) is a critical risk factor for autism spectrum disorders. CNTNAP2 encodes a protein on the surface of neurons that is involved in interactions between neurons and glial cells in axons with a myelin sheath.

Fragile X syndrome, which is closely associated with autism, is a single-gene disorder caused by the lack of a protein that suppresses protein synthesis. A fragile X mouse model has been shown to exhibit increased protein synthesis in the brain.

SHANK mutations and copy number variations (CNVs) — duplications or deletions of stretches of DNA — are linked to autism. Mammals have three SHANK genes, each encoding multiple variants of the SHANK protein expressed by different messenger RNAs. Several mouse SHANK knockouts have been described, but these mutants exhibit inconsistent — and often contradictory — patterns of defects at synapses, or neuronal junctions. Thus, mouse genetic studies have not produced a clear picture of how SHANK proteins regulate the formation or function of synapses. This is most likely due to overlapping functions of the SHANK protein variants.

New protein synthesis is essential for long-lasting memory, and the proteins ERK and mTOR, which regulate gene translation, have a crucial role in this process. Several monogenic syndromes associated with autism, notably fragile X syndrome and tuberous sclerosis complex (TSC), involve proteins that function in these translational regulatory pathways.