|Audiogenic Seizures and Effects of mGluR5 Agonist MPEP in the Fragile X Mouse
by Robert Bauchwitz, 3/1/2004
Dr. Bauchwitz’s work on seizures in Fragile X
mice suggests that mGluR5 antagonists may
effectively treat a range of symptoms of
Fragile X. Much of his current effort is devoted to pre-clinical testing of potential therapeutic
agents in the knockout mouse model. These experiments are the essential "proof-of-principle" which
will enable pharmaceutical development and human trials of several important new classes of therapeutic
compounds for fragile X. This work is enormously labor-intensive, and requires maintenance of the
largest colony of fmr1 knockout mice in the world.
by Rob Bauchwitz, 3/2004
mGluR receptors have been implicated
in the abnormal neuronal responses observed in Fragile X
syndrome. To address whether reversing mGluR signaling
alterations might ameliorate the effects of Fragile X, we
have tested a drug,MPEP, which specifically blocks one
type of group 1 mGluR receptor (mGluR5).
Using MPEP, we have been able to reverse the susceptibility
that Fragile X mice have to audiogenic seizures, which
are triggered by very loud sound.
We have also shown that the degree of rescue is equivalent
to that found by placing a copy of the human FMR1 gene
into the genome of Fragile X mice, suggesting that MPEP
can compensate for lack of FMRP in protecting against
audiogenic seizures.We are also testing the effects of
mGluR5 antagonists in other learning and behavioral assays.
Finally, we are producing new mouse models of Fragile X
which might give more robust learning deficits comparable
to those observed in humans. If that is the case, we will use
such animals to further assess the effectiveness of mGluR
antagonists and other compounds on Fragile X cognition.
By Robert Bauchwitz, 7/2003
Our laboratory specializes in the production and study of
mouse models of Fragile X, to identify treatments for the
disorder in the short term and a cure in the longer term.
We have created 15 FMR1 transgenic mouse lines.
These mice lack the normal mouse FMR1 gene, but
have various portions of the human X chromosome
spanning the FMR1 gene inserted into their
genome. Our goal is to produce a viable FMR1
sequence for use in human gene therapy for Fragile
X syndrome. One of the challenges of gene therapy
is to introduce a new gene (transgene) into cells in
such a way that it functions precisely like the normal
gene, producing the right amount of its protein
product, FMRP, at the right time and in the right cells.We
aim to find the smallest piece of DNA (the FMR1 gene and
regulatory sequences) necessary for the gene to function
properly. Our transgenic mice have already given us important
information on the acceptable and necessary dose of
FMRP which can be present in mice in order to restore
function without causing toxicity. These studies are now
being extended through cognitive testing of the animals.
We have also continued our extensive molecular and
cognitive analysis of the original mouse model for Fragile X,
the FMR1 tm1Cgr mutant.We are assessing the effects of
novel pharmacologic agents on intelligence in these mice.
One agent we are testing is MPEP, which blocks mGluR5, a
receptor involved in protein synthesis dependent LTD (long
term depression). LTD, a response that neurons can make
when stimulated, may be important in Fragile X, since
Huber and Bear have recently shown that it is elevated in
the Fragile X knockout mouse brain.We
are investigating whether blocking the mGluR5 receptor
with MPEP in the Fragile X knockout mice makes their
behavior more similar to that of their otherwise identical
wild type brothers. This is exciting work because MPEP has
the potential to be one of the first drugs to provide an
enhancement of intellectual function in Fragile X.