Fragile X Syndrome - A Cause and Cure?

Doctor Gul Dolen explains that Fragile X syndrome can be considered a disorder of plasticity, mediated by metabotropic glutamate (mGlu) receptors, and potentially treatable with pharmaceuticals.

I’ve been working on plasticity for a really long time. The idea of plasticity has been around for a hundred years; it was first coined by William James who was a psychologist and a philosopher of writing in the late 19th century. He coined the phrase to describe structural changes in the brain that must be there when your brain is learning something. His description basically said that when you learn habits, addictions, even development of the brain, requires these plastic changes. He was explaining this and describing this as a mechanism of how the brain learns before even the synapse had been discovered. So, plasticity has been something that we as a lab had been working on for years, and specifically we had been working on metabotropic glutamate receptors as a molecular target required for certain types of plasticity to happen in the brain. It sort of serendipitously happened that we started working on Fragile X because it was a developmental brain disorder where mental retardation was a prominent feature of the disease. The idea was, well here is a disease where clearly learning and memory [are affected] and therefore it must be that plasticity is disrupted in these. Because we had our interest in mGluR already we started studying them, and it turned out that the plasticity deficit that they had in the mouse model of Fragile X was a mGluR5 (metabotropic glutamate receptor 5) form of plasticity that was disrupted. The way that it was disrupted was sort of a little bit surprising because I think everybody had, maybe in a very American way, assumed that more plasticity is better. It’s in our vernacular too; we say things like “you can’t teach an old dog new tricks” and that’s seen as such a bad thing. But it may turn out that in fact those kinds of breaks on our abilities to learn ‘tricks’ later on in life are important and necessary. Fragile X sort of points to that because we believe that Fragile X is a disease where they have plasticity, and it’s too much plasticity and it’s too much for too long. That exaggerated plasticity is mGluR plasticity, and so our findings have been first of all to show that that was the case, that you have too much plasticity in the Fragile X. Then the second thing was that we can rebalance the plasticity in Fragile X by turning down signaling through the metabotropic glutamate receptors. What’s nice about that is that it gives us a new way of understanding the brain, that you need balance in order to have normal function, and it also suggests that we can treat Fragile X with drugs that modify the metabotropic glutamate receptor in the way that I just described.