Role of a novel Wnt pathway in autism spectrum disorders

Louis Reichardt, Ph.D.
Patricia Janak, Ph.D.
University of California, San Francisco

Many of the symptoms of autism, such as social impairments and repetitive behaviors, are accompanied by abnormal brain activity in the forebrain region. Louis Reichardt at the University of California, San Francisco, and his colleagues plan to study the development of the forebrain, focusing on an important intercellular signaling pathway known as the Wnt pathway.

Named for a family of extracellular signaling molecules, the Wnt pathway can control rearrangements of a cell’s cytoskeleton and the cell adhesion proteins that connect once cell to another. These two processes are necessary to construct the specialized signaling region between neurons known as the synapse. The Wnt pathway has been implicated in synapse formation in the forebrain, in regions such as the hippocampus, which controls memory and anxiety, and in the neocortex, which regulates movements.

One target of the Wnt pathway, a cell adhesion protein called p120 catenin, is stabilized by Wnt signaling and moves to synapses as they are forming and organizes the underlying cytoskeleton. Some cases of autism have been traced back to genes that regulate synapse formation. Reichardt and colleagues showed in 2006 that the neurons of the hippocampus develop fewer synapses when they lack p120 catenin. More recently, they reported that the absence of p120 catenin impairs the localization of synaptic vesicles at synapses and reduces synaptic transmission. Reichardt proposes that disruption of the Wnt pathway prevents p120 catenin from building synapses in the forebrain, disabling the motor, memory and emotional pathways encoded there and potentially causing autism.

He and his team plan to collaborate with three other research groups to study the interactions between p120 catenin and the Wnt pathway in the forebrain and to determine whether defects in this pathway could lead to autism. The researchers plan to analyze how several key components of the Wnt pathway influence synapse formation and the shape of the neurons, which would affect how well the cells communicate to control movements and social interactions. Reichardt and colleagues then plan to evaluate how the behavior of the mice depends on this Wnt pathway activity in the forebrain, specifically looking for autism-like behaviors that result from disrupting the Wnt-p120 catenin pathway. Their findings may shed light on the origins of autism, and may suggest new ways to diagnose and treat the disorder.