Probing a single-gene form of autism from molecules to behavior

  • Awarded: 2008
  • Award Type: Research
  • Award #: 95395

In autism, tracing the connections between the underlying genes, altered brain function and behavioral symptoms is difficult because the disorder is caused by multiple factors in most people. Richard Tsien and Ricardo Dolmetsch of Stanford University in Palo Alto, California, Randall Rasmusson of the State University of New York at Buffalo and their colleagues study a form of the disorder linked to a single mutation, which may provide insights into the other forms of autism caused by many factors.

Timothy syndrome is a rare disorder that arises from a single mutation — G406R — in a calcium channel. The mutation hampers the shutting-off of the channel. About 75 percent of people with Timothy syndrome have autism.

To generate a mouse model of Timothy syndrome and autism, Rasmusson and his colleagues created a mouse line that expresses the G406R-containing calcium channel. Mice with high expression of the channel are stillborn, whereas mice expressing low levels of the G406R calcium channel have normal general health and basic activity, which will allow a thorough evaluation of their development, neural circuitry and behavior. Tsien, Rasmusson and Dolmetsch have undertaken a collaborative, multidisciplinary effort to characterize these mice.

In behavioral studies, Tsien and his group have found that the mice have atypical social behavior and communication, repetitive and persistent actions in navigation tasks, and resistance to a change in the environment. These behaviors are not found in mice expressing low levels of a wild-type calcium channel in control experiments, indicating that the autism-like behaviors are specific to the Timothy syndrome mutation and are not general effects of low calcium channel expression. The results demonstrate that behaviors reminiscent of the classical triad of autism symptoms can arise from a single amino acid replacement in a signaling protein.

In further studies, the researchers propose to use these mice as a starting point to understand the changes in neuronal signaling networks that occur upon expression of the G406R calcium channel. For example, Dolmetsch and his colleagues have found striking changes in the dendritic morphology of cortical neurons. They also plan to attempt to improve autism-like behaviors with interventions during development and in adult mice. These studies may provide important information about the origins of autism and how the disorder may be treated.

Subscribe to our newsletter and receive SFARI funding announcements and news