Dysregulation of the normal immune response appears to underlie the development of a wide variety of neurodegenerative diseases, including autism spectrum disorders (ASDs). Animal models of ASD have demonstrated that maternal infection or abnormal immune signaling contribute to the development of autism-like disorders. Together, these findings suggest that immune response genes play an important role in the generation of ASDs.

All cells, including neurons, possess mechanisms to coordinate protein synthesis with protein degradation to maintain amino acid and protein levels within the appropriate range. Even a subtle imbalance between these processes can disrupt normal neuronal morphology and functions.

Autism arises in early childhood, during a period of intense learning when many of the brain’s connections are modified by experience. Several autism-associated proteins also play important roles in memory formation.

The generation of all-or-none action potentials is critical for proper brain function. At the heart of action potential generation are voltage-gated sodium channels, which underlie the rising, or depolarizing, phase of the action potential. Twelve different mutations in the SCN2A gene, which encodes the neuronal sodium channel NaV1.2, have been identified in two large autism genetic studies.

Abnormal patterns of head and brain growth have been reported in a subset of individuals with autism. A heterogeneous collection of genetic risk factors for autism and micro- and macrocephaly have been identified, including mutations in genes acting in the PI3K-AKT-mTOR (e.g., PTEN) and Wnt-beta-catenin (e.g., CTNNB1, CHD8 and TCF4) signaling pathways.

Opioids have long been implicated in social behaviors. Reducing opioid activity increases affiliative social behaviors and social reward-seeking while lowering stereotypies and self-injurious behaviors. The specific role of opioid blockers in complex social cognition, however, requires more investigation.

It is well established that homeostatic signaling systems interface with the mechanisms of developmental and learning-related plasticity to achieve stable yet flexible neural function and animal behavior. Experimental evidence from organisms as diverse as Drosophila, mice and humans demonstrates that homeostatic signaling systems stabilize neural function through the modulation of synaptic transmission, ion channel abundance and neurotransmitter receptor trafficking. At a fundamental level, if homeostatic plasticity is compromised, the nervous system is likely to be more sensitive to perturbations. Graeme Davis and his colleagues speculate that impaired homeostatic plasticity could contribute to autism by making the developing nervous system vulnerable to perturbations of any origin, including genetic, environmental or immunological stresses.

Multiple autism spectrum disorders share similar neuronal deficits at the molecular and cellular levels. Understanding the mechanism underlying those deficits helps researchers identify valuable targets for therapeutic development.

Autism appears to be caused by a complex interplay of genetic and environmental factors. Over the past decade, scientists have established multiple animal models of autism using both genetic and environmental manipulations, demonstrating the presence of communication and social behavior deficits in these animals, as well as the presence of repetitive behaviors characteristic of individuals with autism. Randy Blakely and his colleagues at Vanderbilt University in Nashville, Tennessee, believe that the activation of a class of enzymes known as p38-alpha MAP kinases (p38-alpha MAPK) may underlie the ability of both genetic and environmental factors to produce autism.