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Consequences of MeCP2 deficiency in the serotonergic system in autism spectrum disorders

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United States

One way researchers can investigate a complex, multi-gene disorder such as autism is to use what is known about related disorders to see if the same mechanisms might be involved. Rett syndrome (RTT) is one of those disorders related to autism. In fact, it's the only disorder among the many classified as autism spectrum disorders (ASDs) with a known genetic cause. Specifically, mutations in a gene responsible for the protein, methyl-CpG binding protein 2 (MeCP2), cause RTT. While it is still unclear how MeCP2 relates to the behavioral impairments characteristic of RTT, a possible explanation is that MeCP2 plays a critical role in particular neurons. One potential group of neurons that influence the kind of behaviors shared by RTT and autism are the serotonergic neurons, which use serotonin to communicate to other neurons to mediate specific aspects of behavior. In order to investigate the role of MeCP2 on serotonergic neurons, the fellow and Dr. Zoghbi will remove MeCP2 from serotonergic neurons in mice and use behavioral analysis of these mice to examine anxiety levels and social withdrawal. They will also use a novel approach called “BACarray” technology to generate mice that will be used to identify genes that are inappropriately expressed in serotonergic neurons in the absence of MeCP2. These genes will be good candidates for further study on their possible role in autism spectrum disorders. What this means for people with autism: These studies will help pinpoint specific behavioral characteristics associated with the absence of normal MeCP2 function in serotonergic neurons. This work may serve as a solid foundation for pre-clinical trials that involve targets of MeCP2 function and expedite the rational design of therapies for these disorders. Dr. Zoghbi's lab was instrumental in discovering that mutations of the MeCP2 gene led to Rett Syndrome, and brings important expertise and a strong training environment for the fellow to the field of autism research.