Although a number of studies have documented abnormal expression of metabolites in blood and urine samples from individuals with autism, no clear metabolic biomarkers or unifying concepts regarding metabolic dysregulation and brain development have emerged from such studies.

James Rand and his colleagues at the Oklahoma Medical Research Foundation studied the functions of a post-synaptic adhesion protein called neuroligin and the consequences of mutations affecting this protein. There are four neuroligin-encoding (NLGN) genes in people, and mutations disrupting NLGN3 and NLGN4 are associated with a subset of autism cases. Rand and his group used the roundworm C. elegans because of its simple nervous system and its ease of genetic and molecular analysis. Many studies have demonstrated that C. elegans neuronal proteins are structural and functional homologs of the corresponding mammalian proteins.

Multiple nucleotide variants in the coding sequence of the EFR3A gene are associated with autism, but the protein's function is not well understood. Pietro De Camilli and his colleagues at Yale University have used their expertise in neuronal signaling and cell biology to uncover the role of EFR3A in autism.

Mark Alter and his colleagues at the University of Pennsylvania study the relationship between brain cell maturation and the transcription of genes. Each cell type has its own transcription program, depending on which genes it uses to function. As brain cells mature, they undergo many changes in their cellular transcription programs.

Two central challenges in autism research are defining specific neuronal abnormalities from genetic and environmental contributions and establishing preclinical models with human cells to test potential therapies. Autism is believed to be a disorder of neurodevelopment with a strong genetic liability. A large number of genetic risk loci have been identified by genetic association studies. Various animal models are being developed to explore the function of these genes in regulating neuronal development.

Rudolf Jaenisch and his colleagues sought to create a novel platform for studying autism spectrum disorders in human cells. Using cutting-edge gene-editing technology, they introduced mutations into genes that are known to cause disorders on the autism spectrum, such as Rett syndrome and fragile X syndrome. This allowed them, for the first time, to investigate the effects of pathogenic mutations on the morphology, electrophysiology and intracellular signaling of human neurons in culture.

Poor reciprocal social interaction is a devastating behavioral anomaly and a defining feature in people with autism spectrum disorders. Little is known about the cause and mechanisms of social deficits in autism, which hampers the development of effective therapies. Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system. It controls excitatory transmission by binding to a family of receptors, including AMPA receptors. Glutamate signaling defects causing an imbalance in excitatory and inhibitory neuronal circuits are implicated in autism; however, the molecular mechanisms remain unknown. The research teams of Richard Huganir and Tao Wang at Johns Hopkins University in Baltimore propose to study mutations in AMPA-receptor signaling genes that have been found in people with autism and to generate mouse models with these human mutations to investigate mechanisms of social deficits in autism.

Animal models offer opportunities to conduct biological studies in order to identify the mechanisms responsible for autism symptoms. Researchers commonly use the BTBR mouse strain as a model for studying mechanisms that may be responsible for the development of autism, because BTBR mice show many autism-like behaviors.