With a $143,000 grant from FRAXA Research Foundation from 2004-2006, Drs. Walter Kaufmann, Richard Huganier, Paul Worley, and David Lieberman at Johns Hopkins University studied the molecular dynamics of mGluRs in areas involved in cognition in the Fragile X knockout mouse.
Metabotropic Glutamate Receptor Function in Fragile X Knockout Mice as a Possible Etiologic Factor in Autism and Glutamate Receptors and Their Associated Postsynaptic Proteins in the FMR1 Knockout Mouse
by Walter Kaufmann, 3/1/2006
To better understand the intellectual and behavioral problems observed in boys with Fragile X syndrome (FXS), we have been conducting studies on several brain regions of the FXS knockout mouse. Our research aims to extend the pioneer work of Dr. Mark Bear that has led to the mGluR Theory. In addition to providing more evidence for the theory, we have found other abnormalities in key metabotropic glutamate receptors and the receiving side of neuronal connections (i.e., synapses) in the brain’s hippocampus and cerebellum. These results suggest that a combination of drugs targeting different glutamate receptors may be necessary for therapy of different neurobehavioral problems.
Furthermore, our data indicate that a fundamental process of neuronal function, termed signaling by the MAPK pathway, could also be abnormal in FXS. Since signaling by the MAPK pathway could be measured in blood cells, if demonstrated to be also abnormal in these cells, our data open the possibility of using blood measures as markers of abnormal function and response to treatment in FXS.
Altogether, our results indicate complex abnormalities in glutamate receptors and associated proteins in several brain regions of the FXS knockout mouse. Despite this complexity, a few abnormal processes that could potentially be measured in blood cells appear to be consistent across brain regions. If the abnormalities found in the FXS mouse are also present in boys with the disorder, our data will serve as a basis for designing new diagnostic and therapeutic strategies for intellectual and behavioral problems in FXS.