For release: Monday, August 14, 2006
A new study shows that inactivating a gene called Pten in a mouse model produces disturbances in social interaction and brain organization that closely mirror human autism and related disorders. This is the first time scientists have developed an animal model with both behavioral and cellular abnormalities similar to autism. These animals could provide important insights into understanding the brain regions and neurochemical interactions that underlie in this mysterious disease.
Children with autism have difficulties with social interaction and verbal and nonverbal communication. They also exhibit repetitive behaviors. These problems can range from mild to disabling. While scientists don’t know what causes autism, it is likely that both genetics and environment play a role. Current evidence suggests that at least a dozen genes may be involved in autism. The researchers in the study focused on one of these genes, called the Pten gene. Pten, best known as a tumor-suppressor gene, plays a role in regulating cell survival, neuronal migration, and nerve fiber growth. The study examines the effects of disrupting the neuronal transmission of a gene and how this disruption affects mouse behavior. The research appears in Neuron* and was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS).
“Autistic individuals who have the PTEN gene mutation are rare. However, we are focusing in on the anatomical area most implicated in the disorder,” says Dr. Luis F. Parada, director of the Center for Developmental Biology at University of Texas Southwestern Medical Center. “Understanding the sequence of reactions and cellular changes in these mutated mice could translate to general findings for human autism.”
Dr. Parada and his colleagues created mice that had the Pten gene inactivated in mature neurons found in brain areas that control learning and memory – the cerebral cortex and hippocampus. The researchers discovered that this selective gene inactivation produced profound behavioral changes in mutant mice. Mice with the Pten deletion showed several examples of reduced social interaction and increased anxiety.
“Mice are normally very socially interactive creatures,” says Dr. Parada. “Even though the mutants were only a small subset of the litter, by the third to fifth week we could identify the mutated mice by sight. Those mice were always the ones hanging out in the corners by themselves or very skittish when handled by the researchers.”
When it is introduced to another mouse, a normal mouse will typically investigate the new mouse by walking over to it and sniffing it. If given a choice between another mouse and an inanimate object like an empty cage, a normal mouse will spend most of its time interacting with the other mouse. Also, if it has a choice about whether to socialize with a new mouse or a familiar mouse, the mouse will prefer the new mouse. In normal mice, this level of interaction or curiosity wanes as the novelty wears off. However, Pten mutant mice react similarly to both the mouse and the inanimate object, even after multiple exposures. The mutated mice consistently show a lack of interest and impairment in interacting socially with other mice. This is accompanied by exaggerated responses to stressful sensory stimuli and increased anxiety in behavioral tests. These characteristics of abnormal social interactions and hypersensitivity to sensory stimuli are hallmarks of human autism.
The researchers also found cellular and neuroanatomical changes in the brains of Pten mutant mice. The mice showed overgrowth of neurons (larger cell bodies, increased axon growth, and abnormal synapses) and an increased number of neuronal interconnections – characteristics also seen in some people with autism. The mice without Pten also had increased brain volumes and enlarged cerebral cortex and hippocampus brain regions. Enlarged head circumference, or macrocephaly, is present in 20 percent of people with autism.
“When neurons are first formed, they send out axons to different places throughout the brain and then are pruned. Maybe the neurons in these mice aren’t getting pruned,” says Dr. Parada. “Neurons that are hyperactive and that interact with abnormal brain regions could lead to cognitive disruptions and to sensory overload.
The Pten mutant mouse model does not mimic all the characteristics seen in people with autism. The mice do not display repetitive behaviors or replicate the developmental nature of the disorder. However, the mouse model can provide a starting point for understanding the role of specific genes and molecular pathways in autism or other social impairment conditions.
Dr. Parada and his colleagues are now planning studies to examine whether drug treatment can alter the behavior of the mutant mice. “Since Pten is a tumor-suppressor gene and exists on a well-studied cancer pathway, we can give drugs to reverse this pathway and observe how they affect the cellular and behavioral abnormalities in these mice,” says Dr. Parada.
The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
*Kwon C-H, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ and Parada LF. “Pten Regulates Neuronal Arborization and Social Interaction in Mice.” Neuron, May 4, 2006, Vol. 50, pp. 377-388.
-by Michelle D. Jones-London, Ph.D.
Last Modified January 31, 2007