Editors' ChoiceAutism Spectrum Disorder

Neurons Themselves May Shy Away from Normal Interactions in Autism

See allHide authors and affiliations

Science Translational Medicine  20 Mar 2013:
Vol. 5, Issue 177, pp. 177ec48
DOI: 10.1126/scitranslmed.3006109

As more genes involved in autism spectrum disorders (ASDs) are identified, a critical next step is to understand how these genetic alterations exert their pathological effects. Timothy syndrome (TS) is a multisystem disorder associated with ASDs that results from a mutation in the gene encoding a subunit for L-type calcium channels found in neurons. Although the mutation itself has been reported in the past, the mechanism by which this mutation changes nervous system development and causes disease was not well understood.

In a recent publication, Krey et al. reported a possible pathogenic mechanism involved in TS. The authors studied neurons from knock-in mice that model TS, as well as rat neurons expressing mutant TS channels and human neurons derived from induced pluripotent stem cells from patients with TS. In all three cases, when neurons that express mutant calcium channels were stimulated, they responded by retracting rather than extending their dendrites the way wild-type neurons do. This is notable because ASDs are frequently associated with abnormalities of dendritic structure and function that are believed to disrupt communication between neurons. Surprisingly, despite the fact that the TS mutation caused excessive calcium influx, and calcium can direct neuronal plasticity, this abnormal pattern of dendritic retraction did not appear to result from altered calcium influx. Instead, the authors showed that the retraction resulted from disrupted interactions between calcium channels and Gem, a small G protein that regulates RhoA signaling.

This elegant combination of studies in rodent models and patient-derived cells reveals how a gene strongly associated with autism can exert cellular effects that correspond to possible pathogenic mechanisms. Because Timothy syndrome represents an extremely rare cause of autism, future studies should examine whether abnormal dendritic retraction may occur in other forms of autism. It is also unclear whether this dendritic retraction is specific to particular classes of neurons. Last, it will be important to link abnormal dendritic retraction to pathological behaviors, possibly by disrupting interactions between calcium channels and Gem in vivo.

J. F. Krey et al., Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat. Neurosci. 16, 201–209 (2013). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article