Current genetic evidence links autism with defects in signaling between brain cells, or neurons, particularly at specialized regions of the neurons known as synapses. Bernardo Sabatini and his colleagues at Harvard Medical School plan to study how neuron activity affects synapse formation, focusing on the roles of three autism-associated proteins, which are members of the Shank, neurexin and neuregulin families.

Most of the genes known to be associated with autism seem to regulate how neurons communicate with each other at structures called synapses. Li-Huei Tsai and her colleagues at the Massachusetts Institute of Technology study the role of CDK5, an enzyme involved in synapse activity, and its influence on SHANK3, another protein known to be important in autism.

Many children with autism have unusually high numbers of synapses, or connections between neurons, particularly in the cortex, which may result from overgrowth and a disruption of neuronal pruning during childhood. Pruning and reshaping of neurons pares down the number of synapses in the brain while eliminating inappropriate synapses that lead to over-connectivity between brain regions, and possibly inappropriate learning, behavior and seizures. David Sulzer and his colleagues at Columbia University hypothesize that autism-associated mutations in the tuberous sclerosis gene, TSC, can cause over-connectivity when the target of TSC, the mTOR pathway, interferes with normal neuronal pruning.

The neurobiology behind the classic signs of autism — repetitive behaviors, impaired social interactions and language deficits — is largely unknown. Based on their studies on a mouse model of obsessive-compulsive disorder, Guoping Feng and his colleagues at Duke University propose that an imbalance between two circuits of neurons may underlie the repetitive behaviors associated with autism.

Autism arises in early childhood, during a period of intense learning when many of the brain’s connections are modified by experience. Eric Kandel, Yun-Beom Choi and Craig Bailey of Columbia University are using animal models of memory formation to investigate how two autism-associated proteins — neuroligin and neurexin — regulate this process.

Like autism, Rett syndrome arises in young children with a progressive loss of skills such as speech and control of movements, and is frequently accompanied by mental retardation and seizures. Mutations in the gene MECP2 are known to cause Rett syndrome. Josh Huang and his colleagues at Cold Spring Harbor Laboratory plan to study how the MECP2 gene regulates brain circuitry — information that may have implications for both Rett syndrome and autism.

Genetic studies have linked several new genes to increased risk of autism. The challenge, however, is in understanding how mutations in these genes disrupt neural development and cause the disorder. Ted Dawson and his colleagues at Johns Hopkins University plan to undertake this task for the signaling protein known as the MET receptor.

Autism arises, at least in part, as a result of poor signaling between neurons, which disrupts the behavioral pathways necessary for social interactions, language development and motor control. At Stanford University, Thomas Südhof and his colleagues plan to study how proteins called neuroligins regulate neuronal signaling, in order to understand their role in those behavioral pathways and in autism.

Viral infection during pregnancy raises the risk of autism in the offspring, suggesting a connection between the maternal immune system and fetal brain development. Paul Patterson of the California Institute of Technology and his colleagues have successfully modeled this scenario in mice. In collaboration with David Amaral’s group at the University of California, Davis, they plan to extend these studies to non-human primates, which are socially and physiologically more similar to humans.

Each person with autism has a unique set of abilities and disabilities, and this heterogeneity has made the finding the genetic causes of the disorder difficult. Daniel Geschwind and his colleagues at the University of California, Los Angeles, plan to look for commonalities in gene expression that might define subgroups of people with autism — information that will aid the search for both the cause of and treatment for autism.