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.

Immune system activity in the central nervous system (CNS) has been implicated in numerous neuroinflammatory diseases. Over the past decade, however, Jonathan Kipnis has found evidence that mice with immune deficiencies also exhibit cognitive impairments.

Disruption in the number and function of brain synapses — the connections between neurons — is a central feature in the development of autism and associated cognitive disabilities. Although our understanding of how brain development differs in autism is not complete, an early overgrowth of neurons and synapses, as well as a failure to prune inappropriate synapses, has been observed in the brains of children with autism and in autism mouse models. At the molecular level, overproduction of key synaptic proteins may contribute to the atypical neural and synaptic growth in autism.

Despite the diversity and the rising prevalence of diagnosed cases of autism, the etiology of the disorder remains an open question. Efforts to understand the pathophysiology of autism have focused on genetic factors. However, considering the tremendous diversity of autism types, it seems likely that the causes of autism spectrum disorders are numerous and perhaps overlapping.

One of the most common genetic causes of autism is the loss or duplication of a small region on human chromosome 16 known as 16p11.2. These genetic changes account for only about 1 percent of all cases of autism, but when present, they frequently result in the disorder.

Inflammation during pregnancy has been suggested as a possible contributing factor in the development of autism spectrum disorders in children. A replica of this phenomenon, called the maternal immune activation (MIA) model, is used to study inflammation-induced behavioral changes in rodents. Identification of key immune components in the MIA model may lead to a better understanding of underlying causes of autism.

Shared exposure to environmental factors appears to have a more prominent role in autism than genetics does. Polybrominated diphenyl ethers (PBDEs) are members of an important group of chemicals used in plastics, textiles, furniture and electronic devices. The global production of PBDEs has reached approximately 148 million pounds per year. PBDEs are used as flame retardants in plastics, to which they do not bind chemically. They can thus leach from polymers and pervasively accumulate in the built environment and ecosystem.

One of the most important steps in postnatal brain development is the formation of the connections between neurons, known as synapses. These connections establish the neural circuits that control behavior. NMDA receptors are key molecules in the development and functioning of synapses that use the neurotransmitter glutamate.