|Specific Tests of the mGluR Hypothesis
by Michael Tranfaglia, 3/1/2007
This research group at Scripps is using the most sophisticated proteomic techniques currently available to understand exactly how the absence of FMRP affects levels of other proteins in neurons. "Our proteomic work is motivated by the fact that the most critical gap in our understanding of the molecular basis of FXS resides in the identification of proteins that are dysregulated in the absence of FMRP. Studies of the mRNAs associated with FMRP suggest that it regulates the synthesis of several proteins that can affect synaptic structure and function. However, the number of validated changes in proteins is relatively small compared to the estimated number of FMRP target mRNAs, and there is as yet no reliable way to estimate protein changes from mRNA data. In addition, mRNA methods are not sensitive to potential changes in proteins encoded by mRNAs that are not FMRP targets. Given these and other considerations, it is likely that many more protein changes are critically involved in producing the synaptic alterations seen in FXS."
This investigation has already led to identification of several proteins that may contribute to the abnormalities in synaptic shape seen in fragile X and also a few proteins which have been implicated in autism. One protein presents a potential opportunity for therapeutic intervention with drugs taht are currently in clinical trials for unrelated indications.
Before he became a Fragile X investigator, Dr. Peter Vanderklish had demonstrated that activation of group I metabotropic glutamate receptors (mGluR1 and mGluR5) could cause rapid changes in dendritic spine shape. In as little as 15 minutes, spines of cultured neurons could become long, thin, and immaturelooking. Since this shape is characteristic of the spine shape previously seen in Fragile X brains, this would appear to support the notion that excessive function of these mGluR pathways might be the primary pathology in Fragile X.
Since 2003 when Dr.Vanderklish attended a Fragile X Banbury meeting, he has been studying neurons from the Fragile X knockout mouse in great depth. Initial studies in his lab have shown therapeutic effects of MPEP (the prototype mGluR5 antagonist) in his model system. One of the most intriguing aspects of this line of inquiry is that it strongly suggests that some structural changes seen in Fragile X brains may not only be treatable, but may reverse surprisingly rapidly with specific treatment.