For me, today began with a jog around the sites of our nation’s capital which mentally prepared me for an intense morning and afternoon absorbing an overwhelming amount of information. I took notes like crazy as I bounced from poster to poster and talk to talk in an effort to find something meaningful about which to write for our followers. I found my inspiration during the last talk I attended which covered epigenetics and neural plasticity as it relates to Rett’s syndrome. During this hour long talk,the number of studies from different sub disciplines of neuroscience and their contribution to the overarching goal of research, namely to cure neurological and psychiatric disorders, amazed me. Because Rett’s syndrome plagues the afflicted with a host of behavioral and neurological problems, it requires contributions from all areas of neuroscience, from the basic affected proteins in animal models to clinical trials involving FDA approved drugs. This talk represented a massive effort by researchers, and I left impressed by the organization and involvement in this monumental effort.
Rett’s syndrome is a sex-linked neurodevelopmental disorder that affects almost exclusively females as males often do not survive to term. In 95% of cases, Rett syndrome is sporadic meaning that the parents of the child are genetically normal. Interestingly, the development of the syndrome does not occur until 6-18 months of age and is marked by small hands and feet as well as decelerated head growth. People affected by this disorder often have gastrointestinal problems, verbal difficulties, accelerated hand movements, and in 50% of cases they are not ambulatory. Rett’s syndrome also has implications for autism spectrum disorder and the two are often confused but not exclusive. The focus of the talk I attended centered on a specific genetic mutation of MeCP2.
The mammalian brain is very sensitive to MeCP2 levels and abnormalities in this protein expression are thought to affect almost every neuronal circuitry in the brain including glutamergic, cholinergic, and GABAergic neuronal systems. Specific knockouts of these circuitries lead to differences in symptoms; however, all symptoms are associated with Rett’s syndrome. Interestingly, increasing MeCP2 levels by twice the amount in a mouse brain can dramatically increase spatial learning in mice, but that comes at a cost for social behavior similar to what you might see in Autism Spectrum Disorder. Treatment options for this syndrome are well underway and amazing advances have been made towards a cure.
MeCP2 dysfunction in Rett’s syndrome is thought to arise from a lack of maintenance in its expression. Early expression of MeCP2 is not sufficient to counteract the deficits from Rett’s syndrome which leads to the conclusion that this protein must be maintained throughout the lifespan. In mice who have normal levels of MeCP2 into adulthood and then are given the drug, Tamoxifen, which removes MeCP2 from neurons in the brain, Rett’s syndrome appears after treatment. Additionally, systems affected by a lack of MeCP2 can also be restored. For instance, in a dysfunctional cholinergic system which produces cognitive deficits in object memory, treatment with an AChE inhibitor in addition to cholinergic receptor agonists can reverse these deficits. This shows that the brain’s systems are still intact and ready to function, so treatment involves restoring proper MeCP2 function, and this can theoretically be done in humans.
I have tried to summarize in as much detail as possible the neurological basis and treatment options for Rett’s syndrome as I learned in this presentation. Though the topic may be dry, I want to mention that many topics in neuroscience often are. It is quite difficult to infuse personality or witty jokes into blog posts concerning a horrible disorder. Nevertheless, the purpose of this blog is to relate the advancements in research to our audience. This segue way leads me into the next portion of this post which discusses the various efforts contributing to such a large undertaking as the cure for Rett’s syndrome.
In some cases, accidents in science have produced amazing discoveries like that of Sarin gas, but for the most part, major advances in science result from grunt work. I began to think during this talk about the extensive human effort that went into this project. Though research scientists get the credit for the discovery, their work would not be possible without animal care technicians cleaning cages and feeding mice or even the truck drivers that carry animals from the breeding facility to the research laboratory. There are chemists designing receptor specific drugs for use in clinical trials and research, but do you see their names on research papers written by neuroscientists? The answer is of course no, and I am not suggesting that we trace every last contribution to a name to give recognition, for that would be an absurd waste of time. Nevertheless, it is important for young people considering jobs in neuroscience to look at the bigger picture. Everything counts in making a discovery, and whether or not credit is given where deserved is against the fundamental purpose of science which is, of course, to benefit human kind. In a project of this magnitude, efforts of many people are left to the references section, but that in no way diminishes the value of their work. Moreover, neuroscience is constantly building on itself. Without Bliss and Lomo discovering long-term potentiation in a petri dish, researches would never have known how to relate this to MeCP2 levels and hippocampal plasticity. In the end, everything counts, and being involved in a project such as this, no matter at what level, is a great honor.