|Pharmacologic Interventions in the Fmr1 KO Mouse
by Catherine Choi , 1/1/2006
As proposed by Mark Bear and his colleagues, dysregulation of metabotropic glutamate receptors (mGluR) may underlie several aspects of Fragile X syndrome. In neuronal synapses FMR1 expression plays an important role in activity-dependent synaptic modifications, as is indicated by its absence leading to enhanced weakening of synapses (long-term depression) that is specifically dependent on mGluR activity. The ability of neuronal synapses to be plastic, that is modify their behavior in accordance with previous inputs and levels of activity, is thought to underlie the phenomenon of learning and memory. Therefore, dysregulation of plasticity in Fragile X may be one of the contributing mechanisms to the cognitive problems associated with the disease.
Recently, we demonstrated in our fruit fly (Drosophila melanogaster) model of Fragile X, which is lacking the single homologous dfmr1 gene, a robust impairment in cognitive function. Using this behavioral readout as a tool, we used the fruit flies to investigate the contribution of enhanced mGluR signaling on their cognitive phenotype. We chronically treated the flies with either antagonists of the Drosophila homolog of mGluRs or with lithium, an agent that inhibits a downstream component of mGluR signaling. Much to our excitement, we found that all of these agents returned cognition to the level of control treated flies, thus supporting the hypothesis that, indeed, the absence of dfmr1 expression contributes to a cognitive impairment phenotype that involves exaggerated mGluR signaling. Our work in the flies indicates that antagonizing mGluR signaling may be a potential pharmacologic strategy.
Our next goal, with the funding from FRAXA, is to investigate the effects of this pharmacologic approach in Fmr1 knockout mice, specifically studying the effects of a mGluR antagonist and lithium on the enhanced mGluR-dependent long-term depression phenotype in the Fmr1 KO mice. We also propose to perform biochemical studies to investigate the effects of these treatments on levels of relevant proteins to further elucidate and validate the mechanisms by which these drugs are having their effects.
Dr. Tom Jongens and colleagues have
obtained remarkable results with their studies of drosophila
mutants -- fruit flies with the equivalent of the Fragile X gene
knocked out show significant impairment in cognitive function,
as shown by studies of their defective courtship behavior. More
importantly, this impairment can be reversed by treatment with
MPEP, an experimental compound which dampens mGluR
function. Furthermore, lithium treatment was also able to
completely rescue this cognitive phenotype. Lithium is a
common psychiatric treatment which is readily available and
may serve to stabilize the mGluR pathways affected by Fragile X.
Of course, humans are not quite the same as fruit flies.
Therefore, Catherine Choi and her collaborators, Sean McBride
and Tom Jongens, are attempting to replicate these results in the
Fragile X knockout mouse. A lithium effect in mice would
probably justify immediate trials in humans with Fragile X. This
$7600 grant will allow the team to purchase Fragile X mice to
test this theory.