Fragile X syndrome afflicts 1 in 2,500 individuals and is the leading heritable cause of
mental retardation worldwide. The overriding clinical manifestation of this disease is mild to severe
cognitive impairment. Age-dependent
cognitive decline has been identified in Fragile X patients, although it has not been fully characterized nor examined in animal models. A Drosophila model of this disease has been shown to display phenotypes bearing similarity to Fragile X symptoms. Most notably, we previously identified naive courtship and
memory deficits in young adults with this model that appear to be due to enhanced
metabotropic glutamate receptor (mGluR) signaling. Herein we have examined age-related
cognitive decline in the Drosophila Fragile X model and found an age-dependent loss of learning during training. We demonstrate that treatment with mGluR antagonists or
lithium can prevent this age-dependent
cognitive impairment. We also show that treatment with mGluR antagonists or
lithium during development alone displays differential efficacy in its ability to rescue naive courtship, learning during training and memory in aged flies. Furthermore, we show that continuous treatment during aging effectively rescues all of these phenotypes. These results indicate that the Drosophila model recapitulates the age-dependent
cognitive decline observed in humans. This places Fragile X in a category with several other diseases that result in age-dependent
cognitive decline. This demonstrates a role for the Drosophila
Fragile X Mental Retardation Protein (dFMR1) in neuronal physiology with regard to cognition during the aging process. Our results indicate that misregulation of mGluR activity may be causative of this age onset decline and strengthens the possibility that mGluR antagonists and
lithium may be potential pharmacologic compounds for counteracting several Fragile X symptoms.