Walter Kaufmann, MD, PhD, Principal Investigator
Richard Huganier, PhD, Co-Investigator
Paul Worley, PhD, Co-Investigator
David Lieberman, PhD, Postdoctoral Fellow
Johns Hopkins University

FRAXA Awards:
 $40,000 in 2006
 $1,000 in 2005, and additional generous support from The Wiser Family
and the Jack Kent Cooke Foundation
 $60,000 in 2004

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.

by Michael Tranfaglia MD, FRAXA Medical Director, 8/2004

This group of investigators has a long-standing interest in the molecular basis of synaptic plasticity, both during development and in cognitive processes (i.e., learning and memory) in the mature brain. In an effort to test the mGluR Theory of Fragile X, they propose to examine the molecular dynamics of mGluRs in areas involved in cognition in the Fragile X knockout mouse.

Since several dendritic proteins which interact with glutamate receptors show altered levels in the Fragile X knockout mouse, the project will focus on these molecular interactions as the potential for abnormal function of synapses in Fragile X. Among the proteins with elevated levels in the knockout mouse is Arc, a key component of synaptic plasticity in dendrites, originally characterized by Drs.Worley and Kaufmann almost a decade ago. By further defining the mechanisms through which synaptic plasticity is changed in Fragile X, new targets for drug development may be identified. Because this project will delineate interactions between different types of glutamate receptors, this work should enable more precise testing of compounds which affect function of glutamate receptors for the treatment of Fragile X.