There is growing support for the idea that both genetic and environmental risk factors contribute to autism. One environmental risk is maternal infection, as validated by large epidemiological studies showing links between infection during pregnancy and autism in the child. Similar associations were found with elevated immune responses in maternal serum or amniotic fluid. Also consistent with an immune pathophysiology are findings of activated microglia — immune cells within the brain — in people with autism, as well as dysregulation of immune-related genes in the brain, cerebral spinal fluid and periphery.

A major goal of autism research is to understand the relationships among genetic etiology, altered developmental trajectory, aberrant neural circuits and behavioral symptoms characteristic of this disorder. Understanding how the functional activity of neural circuits is altered with cell-type resolution is likely to lead to more effective and targeted therapies. Among the neural circuits implicated in autism are ones involving the striatum, a structure buried deep within the brain that contributes to the evaluation and selection of behavior. Additionally, one gene associated with autism is SHANK3, which is important for the connections between neurons, including those within the striatum.

Autism is a complex disorder of many biological causes that results in characteristic behavioral symptoms. However, recent advances in the genetics of autism point to a constellation of genetic causes that converge on a subset of intracellular signaling pathways, including RAS-MAPK and PI3K/AKT, that may all contribute to autism, even if mutations in these pathways on their own may not be sufficient to cause the disorder.

A large number of susceptibility genes for autism and schizophrenia have been identified, although the function of many of these risk factors in regulating neuronal development is not well understood. Copy number variations (CNVs), structural rearrangements of the genome in which entire chromosomal regions may be either deleted or duplicated, produce variability in the expression level of affected genes.

A rapidly increasing number of genes are implicated in autism. While null alleles —those with mutations that eliminate gene function — tightly linked to autism are extremely helpful in identifying causative genes, one can’t predict the in vivo effects of other types of alleles (such as those with mutations that change the function of the gene).

Nerve cells communicate with each other via excitatory and inhibitory signals. Growing evidence supports the hypothesis that a neuronal excitation/inhibition imbalance resulting in increased excitation in certain nerve cells in the brain is sufficient to elicit autism-like symptoms. Uwe Rudolph and his colleagues at McLean Hospital and Harvard Medical School focus on receptors for the major inhibitory neurotransmitter in the central nervous system, gamma-aminobutyric acid (GABA).

Studies have identified a large number of genes that contribute to autism, and many affect communication between neurons, known as synaptic transmission. However, we do not understand the mechanisms responsible for the genes’ effects on synaptic transmission or how these effects give rise to abnormal behavior. To elucidate these mechanisms, Robert Edwards and his group at the University of California, San Francisco plan to study a protein of known biochemical function that has been implicated in autism and determine its role in synaptic physiology and behavior.

Autism is most likely caused by changes in the development of the cerebral cortex, particularly in neural circuits that process social and cognitive information. Under- or over-connectivity in these circuits has been found in the brains of children and adults with autism. It remains unknown how altered development might lead to these disrupted connections. This knowledge is crucial for new diagnostic, preventive and therapeutic approaches in autism.

A small protein called ubiquitin is added to other proteins to modify their function, causing changes in cellular behavior. Often, the addition of ubiquitin leads to the complete destruction of the tagged protein. This process, called ubiquitination, plays an important role in regulating the abundance of many proteins at neuronal junctions, or synapses, including receptors within the postsynaptic density (a brain region that contains receptors and other proteins that regulate neuronal function).