Autism spectrum disorders comprise a wide constellation of neurobehavioral conditions that arise from abnormal patterns of brain development. In order to understand how autism-related behaviors emerge from alterations to the normal development of the brain, it is necessary to examine how neurons differ in their patterns of connectivity among various brain regions.
Clinicians rely on a triad of behavioral characteristics for the diagnosis of autism spectrum disorders: impaired social interaction, impaired language and communication, and restricted interests and repetitive movements. However, a much broader range of behaviors has been documented in people with autism. For example, individuals with autism can discriminate slightly different grating patterns better than typically developing individuals can, but they struggle to distinguish different facial emotions.
The brain consists of two main types of cells, neurons and glia. Although neurons have been extensively studied, the contribution of glial cells to autism is not well understood. To address this deficit in knowledge, Erik Ullian and his colleagues proposed to investigate the developmental profile and functional properties of a special type of glial cell called an oligodendrocyte (OC), a specialized cell that enwraps axons with an insulating sheath that is essential for proper brain function and the transmission of signals among brain regions.
The most prevalent genetic form of mental retardation, fragile X syndrome, is a single-gene disorder leading to loss of the RNA-binding protein FMRP. Loss of FMRP results in improper messenger RNA (mRNA) translation at synapses — the junctions between nerve cells — synaptic dysfunction, impaired cognitive function and autism-associated behaviors. To investigate the role of synaptic mRNA translation in normal synapse development, mRNAs and their functions need to be identified. While studies have examined the mRNA populations localized to synapses in rodent model systems, the identity of mRNAs at human synapses is unknown.
One of the most common symptoms shared among the autism spectrum disorders (ASD) is difficulty with social interaction. Frequently, this difficulty extends to problems perceiving and producing spoken language. The neural mechanisms for perceiving speech are not well understood, so how the genetic and developmental causes of ASD give rise to this symptom is not known. Stephen Shea and his colleagues at Cold Spring Harbor Laboratory in New York are using a mouse model of ASD to help close this gap in our understanding.
Lauren Weiss and her colleagues used a ‘pathway’ approach — looking at a group of genes connected in a defined biological pathway — to investigate the role of the RAS/MAPK signaling pathway in autism traits. This pathway controls many cellular functions. The researchers compared a large sample representing individuals with RASopathies — genetic, developmental disorders caused by mutations activating the RAS/MAPK pathway — with unaffected siblings and individuals with autism.
Genetic alterations in the tuberous sclerosis complex (TSC) genes, key mediators of protein synthesis, are strongly associated with autism spectrum disorders. Peter Sims and his colleagues at Columbia University Medical Center have developed a novel strategy for cell-type-specific profiling of protein synthesis in the brain, combining ribosome profiling with computational tools.
Mutations in different types of chromatin regulators are associated with autism. In many cases, the mutation disrupts the expression of one copy of the gene or causes a reduction in the expression of the protein.
Findings from autism genetics and the study of animal models of autism suggest that some biochemical pathways are commonly affected in people with autism. The ERK signaling pathway is one such pathway. It mediates the transmission of signals from cell-surface receptors to the cytoplasm and nucleus of cells. ERK signaling regulates diverse cellular processes such as cell proliferation, differentiation and survival; and in the nervous system, it is involved in cognitive function and memory formation.
Autism spectrum disorders are heterogeneous neurodevelopmental syndromes characterized by repetitive behaviors and deficits in language development and social interaction. Studies in people with the disorder have implicated a number of candidate mutations, and researchers have engineered mice that harbor these genetic defects. Validation of these mouse models, however, requires detailed behavioral analyses that quantify both solitary and social behaviors.