Of Mice and Men and Girls and Autism

Elizabeth DiRico

To initiate Trinity College’s celebratory Twenty-Five years of Neuroscience series president Joanne Berger-Sweeney discussed the extensive research that she has conducted on Rett syndrome over the past 15 years. A pervasive neurodevelopment disorder categorized on the autism spectrum that plagues young girls. Symptoms of Rett syndrome typically appear around six months of age, including purposeless arm motions, difficulty with speech and slow cognitive development.

The cause of this disorder is a mutation to the MECP2 gene, a repressible gene that is responsible for producing and regulating MECP2 protein production as well as additional protein production. A random mutation in the MECP2 gene results in inappropriate regulation of protein synthesis, the operon has no ability to turn off DNA transcription and excessive protein is produced. There are significant repercussions for this single gene mutation because MECP2 is an essential protein in neurological development. The bodies inability to regulate gene production impairs the nerve cells and resonates in the form of debilitating neurological symptoms. Due to the genes location on the X chromosome, Rett syndrome is exclusively observed in girls. Girls second X chromosome is essential for compensating for the mutation, where as males do not have the second set of genes and are not able to survive such a crippling mutation.

President Berger-Sweeney first set out to investigate the effect of acetylcholine on MECP2 function. A major hurdle she encountered in her early experimental design was choosing a test subject that would closely mirror human symptoms. Her decision to use mice as a test models opposed to rats based on a more extensively sequenced genetic code, set her ahead of her time. The MECP2 mutant mice produced many symptoms of Rett patients right down to the stereotypical hand grabbing customary to young girls with Rett syndrome.

The effect of acetylcholine was investigated by feeding choline supplements to pregnant mice. The results demonstrated an overall improvement including increased brain volume, motor coordination, growth factors and neuronal health. In her published research, her finding showed that Choline supplements played a role in regulating DNA and histone methylation. She aimed to take this approach a step further my implementing chromatin remodeling drugs in place of supplements to better control DNA and histone methylation. Following the tremendously impressive results of the previous studies, President Berger-Sweeney began experimenting with Acetyl-L-Carnitine a drug she described as “choline on steroids”. Instead of a supplement, this drug was injected a does per day for thirty-six days. The results pertained form these experiments were even more impressive than the previous experiments. The overall health of mutant mice brain improved continuously up until day thirty, dendrites were examined and found to be longer and more extensively branched than before. The take away message was that the key to reversing the effects of Rett syndrome is early intervention.

Although President Berger-Sweeny is at the forefront in Rett syndrome research and has yielded impressive results, in terms of improving Rett syndrome, she will not be satisfied until she finds a cure. She spoke of feeling both an obligation and a connection to the girls who suffer from Rett syndrome. For her future research she hopes to explore the carbon metabolic cycle and believes that this process may play a role in the underlying mechanism of many developmental disorders, including Rett syndrome. Although President Berger-Sweeny has taken off her lab coat in order to step in to an administrative role, she fully intends to return to her research in some capacity.

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