Making connections

Kenney and Frankland. eLife 2014;3:e05504. DOI: 10.7554/eLife.05504 1 of 3 Autism spectrum disorders—such as Asperger syndrome and childhood autism—have long been known to have a significant genetic component (Ronald and Hoekstra, 2011). However, the biological basis of these disorders has remained largely elusive. Hundreds of genes have been linked to autism spectrum disorders (or ASDs), but most only contribute a small increase in risk (Devlin and Scherer, 2012). It has been proposed that ASDs are caused by the abnormal development or dysfunction of synapses: these are the connections between neurons that allow chemical signals to be sent from one neuron to another in the brain (Sudhof, 2008). The dysfunction is thought to lead to a change in the relative numbers of excitatory and inhibitory signals received by neurons. Now, in eLife, Roman Giger and colleagues at the University of Michigan School of Medicine and the Johns Hopkins University School of Medicine report additional evidence for a link between ASDs and dysfunctional synapses (Duan et al., 2014). Previous studies have shown that small genetic differences near a human gene called SEMA5A confer an increased risk for ASDs. It has also been shown that SEMA5A expression is reduced in the brains of people with ASDs (Weiss et al., 2009). The SEMA5A gene encodes a transmembrane protein called Semaphorin 5A that is important for guiding the branches of neurons during development (Kantor et al., 2004). Consistent with a prominent role of synapses in ASDs, Giger and colleagues—who include Yuntoa Duan and ShihHsiu Wang as joint first authors—report that deleting the Sema5A gene from mice results in an increase in the density of synapses and in increased transmission of excitatory signals across synapses (Figure 1). The increase in synaptic density appears in granule cells in a region of the brain called the dentate gyrus, which is found in the hippocampus. At the behavioural level, ASDs are characterised by a combination of abnormal social interactions, difficulties with communication and repetitive behaviours. Alterations in ASD genes related to synaptic function typically result in deficits in social interactions in mice (Ey et al., 2011). Consistent with this previous work, Duan, Wang et al. report that mice in which the Sema5A gene has been ‘knocked-out’ perform poorly in a social preference task, but show normal levels of performance in several other learning tasks or behaviours. Such specific deficits suggest that different behaviours observed in ASDs may be underpinned by distinct biological processes. However, it is not clear how an increase in the synaptic density in granule cells of the dentate gyrus leads to deficits in social interactions. The traditional view of developmental disorders of the brain and nervous system holds that Copyright Kenney and Frankland. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. INSIGHT