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Most readers of this blog have a personal connection with someone who suffers from Rett Syndrome and we tend to equate the function of MECP2 with the symptoms of this disorder. But in fact, what occurs as a result of mutations in a particular gene may be startlingly different from how fluctuations in expression levels of that same gene may manifest.
We know that MECP2 mutations may sometimes be found in disorders beyond Rett such as classic autism, schizophrenia, bipolar disease, and learning disabilities.
Now, two intriguing papers published online August 15, 2010 in Nature Neuroscience have broadened the scope of MECP2 even further by studying its role in drug addiction in rodent models. One paper demonstrates that MeCP2 interacts with a particular micro RNA to control an individual’s desire to consume cocaine. Micro RNAs (miRNAs) are naturally-occurring small transcripts that do not make protein, but bind to specific messenger RNAs to regulate their expression. The second paper suggests that MeCP2 helps to regulate the rewarding properties of psychostimulant drugs, and that subtle changes in protein levels result in significant behavioral changes.
It is my hope that these new data will entice more scientists to study MeCP2. Whether their field of interest is drug addiction, mental health or other areas, their work may help to elucidate the normal functions of MeCP2.
- Rett Syndrome happens when the MeCP2 protein goes awry in development, but MeCP2 is also involved in other complex functions. MeCP2 is important for changes in how the brain works – even in adulthood.
- MeCP2 plays a role in drug addiction
- MeCP2 helps to regulate the rewarding properties of psychostimulant drugs
- The study of MeCP2 outside of Rett Syndrome is important for the Rett field because it brings in a larger pool of researchers and looks at a wider scope of MeCP2’s function.
Below are excerpts from interviews recently conducted by Monica Coenraads with the senior authors of the papers, Paul Kenny and Anne West, and with Eric Nestler, one of the most respected scientists working in drug addiction today.
Paul Kenny, PhD is a neuroscientist in the Department of Molecular Therapeutics at Scripps Florida who studies the underlying molecular mechanisms of drug addiction.
MC: Congratulations on your recent paper, which has received considerable attention. It comes on the heels of another high- profile paper, published in July in Nature. Can you elaborate a bit on the key highlights of your findings?
PK: This paper is in fact an extension of the Nature paper. In that paper we found that a micro RNA, MIR212, is increased in the dorsal striatum of animals that over- consume cocaine and appear to be developing addictive behaviors. It appears that MIR212 is a novel anti-addiction mechanism – it helps to blunt addiction. We wanted to know what the regulatory mechanisms of MIR212 are and if boosting MIR212 production is possible, thereby making animals, and hopefully people, more resistant to addiction. So that set the background for the current paper. We looked in the literature and there was some evidence to suggest that perhaps MeCP2 could regulate the amount of MIR212 and therefore be involved in modulating drug addiction.
MC: Is MIR212 a druggable target that industry could pursue?
PK: The work is very preliminary but there are several companies that are developing therapeutics by mimicking or modulating the activity of miRNA. The challenge is getting this therapeutic into the brain – tough, but feasible.
MC: Would it be correct to say that you came across MeCP2 during the course of your work? You didn’t intentionally set out looking to see if MeCP2 was involved.
PK: Precisely. We did not set out a priori looking for this protein. My lab’s focus is micro RNA and since MeCP2 appears to be a target of MIR212 we have been drawn to this gene. It appears that MeCP2 and microRNA are incorporated into a much larger circuitry that we are trying to delineate. Because of that, we keep coming back to MeCP2 and are therefore expanding our efforts in this area, much more so than I would have anticipated a year ago. Our focus on MeCP2 is not in the context of Rett, of course, but rather addiction and other behavioral disorders. But I’m really confident that the type of work we do and that others are doing will have benefits for Rett research.
MC: The function of MeCP2 remains rather elusive. Whether this protein operates in a gene- specific way or more globally remains a question open to debate. Does your work add any data to this argument?
PK: In my opinion I think the more important question is not whether MeCP2 regulates a specific gene or not, but whether there are whole networks of genes that are regulated. If you think in terms of networks of related genes that influence common outputs, then the problem becomes more tractable. Say that MeCP2 is involved in a program of neuronal activity – for example, an aspect of neuroplasticity – then, there may be multiple ways to damage or enhance that pathway. Rather than chasing a single gene, you may be able to hit a given program in a neuron, and there may be multiple small molecules that may hit that program.
MC: Does a potential connection between MeCP2 and drug addiction have any bearing on Rett Syndrome?
PK: The “handle” on MeCP2 is obviously Rett Syndrome and when most scientists think about MeCP2, they think about it in the context of Rett. But in fact, Rett is what happens when MeCP2 goes awry in development, but the protein itself is involved in other complex programs of neuroplasticity. So the take- home message of our paper is that MeCP2 is really important for changes in how the brain works even in adulthood. If you don’t have MeCP2 your brain doesn’t respond in the same manner to external stimuli. So the question is: Can we circumvent those changes? Can we overcome the deficits through perhaps replacement of MeCP2 or modulating miRNA function, or can we turn on/off some signaling cascade. How we circumvent the deficits may have relevance to Rett. Scientists are working on these possible approaches.
MC: Your paper was published in the same issue as Anne West’s paper. Although her lab was looking at a different brain region, different drug and using different tools, she also is studying the relationship between drug addiction and MeCP2. How did you learn about Anne West’s work?
PK: Last year I was asked to give a talk by NIDA [National Institute on Drug Addiction – part of the NIH] at the Society for Neuroscience meeting. After my presentation on miRNA and epigenetics, a post-doc from the West lab came up to me and told me that they were working on similar things. Anne and I got in touch after the meeting. Coincidentally, we both submitted to Nature Neuroscience. The timing was great and we published in the same issue. We are continuing to stay in touch.
MC: I’d like to go back to the concept of MeCP2 being connected to Rett Syndrome. Is that a good thing or can it be harmful?
PK: Having a gene associated with a disease, especially if it’s a single gene, gives a field a major boost. On the other hand it can be a double- edged sword, to some degree. Sometimes when a gene is associated with a particular disease it gets “labeled” and only people who are interested in that disorder end up working on it. I’m making a broad generalization, but to some degree it applies to me. For a long time, I thought of MeCP2 as a protein involved in Rett but that’s not the whole story, as my paper and Anne’s paper suggest. MeCP2 plays a role in neuroplasticity in the adult brain independent of any developmental disorder. It regulates proper and natural function in the brain.
MC: From the perspective of a parent of a child with Rett and as someone who is eager to stimulate the research efforts behind this disorder I welcome anyone who is working on MeCP2 regardless of what their interest stems from. I wish you all the best on your work and look forward to bringing our readers an update. Judging from your publication record you will have some relevant news for us soon!
We turn now to Anne West, who is in the Department of Neurobiology at Duke University. She did post-doctoral work in Michael Greenberg’s lab at Harvard; he is one of the researchers who first established a link between MeCP2 and BDNF and is working on uncovering the function of MeCP2.
The goal of the West lab is to understand at a cellular level how neuronal activity regulates the formation and maturation of synapses during brain development.
MC: Congratulations to you and your lab on your recent paper. Unlike Paul Kenny who did not a priori set out to look at MeCP2, you had a specific hypothesis that you wanted to test regarding this protein.
AW: That’s right. We are interested in understanding synaptic plasticity: how cells alter their long-term synaptic connectivity in response to something around them. This happens for example when a person goes out and experiences the visual world; that will cause changes in the firing of neurons that change the connectivity of the visual cortex. The activity-dependence of synaptic connectivity is well documented during development, and there has been the idea that perhaps this process by which the brain develops in response to neural activity may be altered in Rett Syndrome. In our case, we were making the assumption that the mechanisms that control synapses might be conserved between development and in the adult brain, and that similar mechanisms might be important in regulating synapses in response to another stimulus—in this case the stimulus is the drug itself. So we really took this as a paradigm that we could use to understand how MeCP2 might regulate synapses in response to an extracellular stimulus, thinking that if we could find some principles, they might apply during development as well.
MC: Were you surprised by any of the findings?
AW: Yes, we were. The Greenberg lab, where I trained, had previously shown that MeCP2 could be phosphorylated. We hypothesized that phosphorylation might be a mechanism by which cells sense something in their external environment, and change in response to that signal. We wanted to work in a paradigm where an extracellular signal would cause a physiologically relevant change in the animal, and then we could study the phosphorylation in that context and try to understand what it was doing.
We expected that if we gave a stimulus—- in our study we used amphetamine—we’d see the induction of phosphorylation of MeCP2, so that part was not a surprise. What was surprising was that we didn’t see phosphorylation everywhere but only in a small population of cells. It was very selective: only in a brain region responsible for the rewarding properties of the drug, and within that region we saw phosphorylation only in a particular type of cell called GABAergic interneurons, which constitute 1 to 2 % of cells in that region. These cells play an important function in terms of the physiological properties of this brain region. We don’t
yet fully understand the functional consequences of regulating MeCP2 in this cell population. But I suspect that we will learn something about the neural networks that underlie behaviors in drug addiction by using phosphorylation as a tool. In addition, studying MeCP2’s function in these cells may lead us to a better understanding of what MeCP2 is doing.
The other surprise was what we observed when, using viruses, we were able to increase or decrease the expression level of MeCP2 in specific brain regions in mice. Using a behavioral test that measures the rewarding properties of amphetamine, we found that if you reduced the level of the protein, the reward the animals experienced from taking the drug increased. On the other hand, when we increased levels of MeCP2, the animals had a decreased sense of reward from consuming the drug. So in essence the body may use MeCP2 as a way to reset the reward threshold and therefore maintain balance.
Finally we also saw that MeCP2 levels modulate the number of synapses in the nucleus accumbens, the part of the brain that is responsible for reward. Specifically, in one of the Rett mutant animals, the 308 mutant made by the Zoghbi lab, we found that there was a significant increase in the number of GABAergic synapses in this brain region.
MC: What do you think are the next steps and how might they be relevant for Rett Syndrome?
AW: Both my paper and Paul Kenny’s showed that regulating the levels of MeCP2 in specific brain regions affects behavior. I hope this will create more interest in understanding the mechanisms by which the levels of MeCP2 are regulated, and why a small change of expression in MeCP2 has an effect. Knowing this would have relevance to Rett.
MC: We wish you Godspeed in your work, and look forward to connecting with you soon for a progress update.
Finally, we turn to Eric Nestler for his valuable perspective on how these data on drug addiction might spur further interest in MeCP2. Dr. Nestler is a pioneer scientist in the field of drug addiction who has made seminal discoveries that have formed the foundation for understanding the molecular basis of depression and drug addiction. He is the Nash Family Professor of Neuroscience, Chairman of the Department of Neuroscience and Director of the Brain Institute at the Mount Sinai Medical Center in New York.
EN: I wrote a News and Views article in Nature Neuroscience on the Kenny and West papers, and I’m very familiar with the data. My own lab just published a paper in Nature Neuroscience as well, showing that DNA methyltransferase [the enzyme that attaches methyl groups to DNA] is also involved in modulating drug addiction. The findings in these three papers are very consistent.
MC: Is the involvement of epigenetics a new concept in drug addiction?
EN: Yes, it is. We published the first paper implicating an epigenetic mechanism, histone acetylation, in addiction models in 2005. What is happening now is that through the study of epigenetic mechanisms we are led toward more and more targets that could potentially be exploited for new treatments. Undoubtedly there will be a significant increase in the number of researchers looking at the effects of MECP2 in areas of the brain they are specialized in exploring.
I think the drug addiction field will be interested in pursuing the larger spectrum of epigenetic mechanisms in drug abuse. These papers extend our appreciation of the involvement of epigenetic regulation and implicate some new mechanisms. I expect that many more investigators will be following up on these ideas.
NOTE: Monica Coenraads will be presenting on this topic at the Tri-State Rett Syndrome Center (Bronx, NY) Parent Gathering on September 26, 2010.