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Oct 13, 2009

Gene Deletion Associated with Autistic and Schizophrenic Behaviors in Mice

  • Researchers at Standford University School of Medicine have discovered how a gene associated with both autism and schizophrenia influences behavior in mice. The team characterized key neurophysiological changes caused by the deletion of this gene, which encodes the protein neurexin-1alpha, in bioengineered mice. They then identified behaviors in the mice that are similar to some symptoms of autism and schizophrenia. 

    The study was published online on October 12 in the Proceedings of the National Academy of Sciences and is titled “Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments.”

    Mutations in hundreds of genes appear to be able to cause the symptoms of autism and schizophrenia, suggesting an unprecedented heterogeneity. Thomas Sudhof, M.D., who led this research effort, suspects that while the number of different genes involved is large, the protein products of these genes participate in a much smaller number of common pathways. Thus, two genes may encode two proteins that seem totally unrelated but in fact interact closely. A deficiency in either’s function could result in the same outward defect. 

    Several large, independent genetic studies have shown that the deletion of the gene encoding neurexin-1alpha occurs in about 0.5 percent of autism cases but not at all in healthy people, according to the investigators. One-half of a percent is more than most other genes contributing to autism, Dr. Sudhof says. “Because of our longstanding interest in neurexin-1alpha, we already had mice that were bioengineered to be lacking in neurexin-1alpha. So we decided to look closely at those mice to see whether this genetic deficiency led to any changes in communication between neurons, and if so, whether the disrupted or altered communication was correlated with any observable behavioral abnormalities reminiscent of those associated with human cognitive disorders such as autism or schizophrenia.” 

    The investigators compared hippocampi in mutant mice brains with their counterparts in a control group of normal mice and made several observations. In this brain region, Dr. Sudhof notes, the mutant mice had alterations in their synapses. The defect was confined to excitatory synapses, rather than inhibitory. “This selective change in the strength of one type of synapse but not the other type alters the balance between the two,” explains Dr. Sudhof. 

    Just as autistic or schizophrenic patients are in many respects normal, mice lacking the neurexin-1alpha gene were not grossly dysfunctional or survival-challenged. “The deletion didn’t leave the mice unable to eat or to learn or to mate and procreate. If anything, they were actually better than the control mice at executing tasks requiring motor coordination,” such as balancing atop a rotating rod without falling off, Dr. Sudhof adds. 

    Importantly, though, the mutant mice exhibited discrete behavioral differences—repeated stereotypical behaviors such as self-grooming and impaired nest-building activity—suggestive of those associated with autism or schizophrenia, according to Dr. Sudhof. 

    Having demonstrated that the neurophysiological effects of neurexin-1alpha, which is already strongly implicated in autism and schizophrenia, correspond to behavioral abnormalities reminiscent of these cognitive disorders, Dr. Sudhof plans to use a new $1.65 million NIH grant to find out if other genes affect the nervous system. The investigators plan to use established techniques to inactivate or increase the activity of 81 autism-associated genes in cultured mouse neurons and then assess whether these changes affect neural development, synapse density, and synapse function. If any of these effects are found, the gene modifications will be tested in whole mice.

     



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