With $48,600 in grants from FRAXA Research Foundation over 2004-2006, Dr. Catherine Choi at Drexel University tested pharmacological treatments in fragile X knockout mice to determine future treatment targets for fragile X syndrome in humans.
As proposed by Mark Bear and 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.
FMRP-mediated Dendritic Protein Synthesis required for Correct Morphological Development in Neurons
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, attempted to replicate these results in the fragile X knockout mouse. A lithium effect in mice could justify immediate trials in humans with fragile X. This $7,600 grant allowed the team to purchase fragile X mice to test this theory.