Autism spectrum disorders (ASDs) are common neurological disorders that include autistic disorder, Asperger disorder and PDD-NOS (pervasive developmental disorder-not otherwise specified). The Centers for Disease Control and Prevention now estimate an overall ASD prevalence of 1 case per 110 children. The three essential criteria for an ASD diagnosis are: (1) impaired verbal and nonverbal communication; (2) impaired social interaction; and (3) restricted, repetitive and stereotyped patterns of behavior, interests and activities. Family studies show that ASDs have a strong hereditary basis, apparently involving a large number of genes. However, it is also clear that environmental factors play a significant role in the etiology and severity of these disorders.

Mutations affecting structural components of synapses are significant risk factors for developing ASDs. The best-studied of these are the neuroligins: postsynaptic adhesion/signaling proteins that bind specifically to a set of presynaptic membrane proteins called neurexins. There are four neuroligin-encoding (NLGN) genes in humans, and mutations disrupting NLGN3 and NLGN4 are associated with autism. However, it is not clear how disruption of a broadly expressed synaptic protein results in the relatively specific behavioral deficits associated with ASDs.

Here, the authors investigate the effects of neuroligin-disrupting mutations in Caenorhabditis elegans. C. elegans neuronal proteins are structural and functional homologs of mammalian proteins, making it a powerful model for analyzing synapse structure, function and development. Worms have a single neuroligin gene (nlg-1), and C. elegans neuroligin is structurally similar to mammalian homologs. Mutants lacking the neuroligin protein have superficially normal growth and behavior, and apparently normal nervous systems. However, the authors show that nlg-1 null mutants have several sensory deficits: they do not respond normally to some chemical cues, they are insensitive to temperature changes and they have altered processing of conflicting sensory inputs.

nlg-1 mutants also have increased levels of oxidative stress, which results from excessive free radicals and reactive oxygen species (ROS) that can damage cellular components (e.g. proteins, lipids and DNA). nlg-1 mutants are hypersensitive to paraquat toxicity (an herbicide that produces excess free radicals and ROS) suggesting elevated levels of endogenous free radicals. Oxidative damage to proteins in nlg-1 mutants is elevated compared with wild-type animals, and mutants are also hypersensitive to the toxic effects of copper- and mercury-containing compounds.

The relationship between ASDs and oxidative stress is unclear, although it has been proposed that oxidative stress, from environmental toxins, may contribute to the disorders. These studies show that loss of the synaptic protein neuroligin causes oxidative stress. This raises the possibility that specific types of neuronal disruption might be the cause, rather than the result, of oxidative stress. In addition, these data demonstrate a clear connection between an autism-associated synaptic mutation in C. elegans and hypersensitivity to environmental toxins (e.g. paraquat, mercury compounds, etc.). This provides an important example of how both genetic and environmental contributions to a neurological disorder can have a single underlying basis.

ASDs are often associated with changes in sensitivity to sensory inputs, as well as the ability to process and integrate these inputs. It is therefore intriguing that nlg-1 mutants have specific sensory deficits, as well as deficits in the processing of conflicting sensory inputs. This characterization of a C. elegans ASD model indicates a role for neuroligin in processing sensory information and the importance of proper synaptic function in regulating oxidative stress.