|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.
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
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
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.