In most cases of autism, the cause is unknown. However, a number of rare syndromes caused by known genetic abnormalities include features of autism, and understanding the mechanism by which these syndromic forms develop may provide insight into autism more generally.

Although the clinical manifestations of autism spectrum disorders are highly variable and their underlying causes are still largely unknown, accumulating evidence implicates variations in genes encoding synaptic proteins, which function at the connections between brain cells. Altered synaptic proteins can lead to faulty wiring in the developing brain.

The development of brain cell connections, or synapses, occurs during the third trimester of gestation and throughout the first few years of life. Proper synaptic formation and brain wiring require a complex interaction between brain activity, usually driven by sensory experience, and genes.

The development of brain cell connections, or synapses, in humans occurs during the third trimester of prenatal life and throughout the first few years of life. Proper synaptic formation and brain wiring requires a complex interaction between brain activity, usually driven by sensory experience, and genes. Many of the genes whose mutations are linked to autism play a role in synapse formation or pruning during brain development. Some people with autism show an excess of synapses, consistent with a deficit in synaptic pruning. Synaptic pruning is a normal developmental process that results in the elimination of inappropriate or unused synapses.

CNTNAP2 is a gene that encodes a member of the neurexin family of proteins and has been implicated in autism spectrum disorders. Neurexins function in the vertebrate nervous system as cell adhesion molecules and receptors. CNTNAP2 is expressed in the region where precursor cells of the neocortex (the outer layer of the brain) originate during embryogenesis, suggesting that it has a role in regulating neural stem cells.

Autism is a syndrome with many causes. David Sulzer and his colleagues at Columbia University examined their new hypothesis that some of these processes converge during a developmental period from early childhood through adolescence when cortical synapses — the connections that provide for communication between neurons — lose approximately half of their overall density, a phenomenon known as ‘synaptic pruning.’

New protein synthesis is essential for long-lasting memory, and regulation of neuronal translation by the ERK and mTOR signaling pathways plays 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.

Autism spectrum disorders are a clinically heterogeneous group of disorders that share common features. Only an estimated 10 to 15 percent of autism cases are monogenic — caused by mutations in a single gene — but the molecular alterations in these disorders could reveal common pathogenic mechanisms shared across the spectrum.

Functional brain imaging studies of individuals with autism suggest that brain activity in response to sensory stimuli is delayed, multisensory brain responses are integrated over a longer time frame, and activity across brain regions is less synchronous than in typically developing people.