Modeling human memory disorders in Drosophila melanogaster, and the restoration of memory in these models by pharmacological treatments

Abstract

Fragile X syndrome and Alzheimer's disease (AD) are two of the more common diseases that limit the cognitive processes of afflicted patients worldwide. We are utilizing the model organism Drosophila melanogaster to model each of these diseases, in order to expediate the identification of novel therapeutic targets for the treatment of Fragile X syndrome and Alzheimer's disease. Fragile X syndrome is a leading heritable cause of mental retardation and is caused by the loss of FMR1 gene function. A Drosophila model for Fragile X syndrome, based on the loss of dfmr1 expression, exhibits several phenotypes that bear similarity to Fragile X-related symptoms. Herein, we demonstrate that treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium can rescue courtship (social interaction) and mushroom body defects observed in these flies. Furthermore, we demonstrate that dfmr1 mutants display cognitive deficits in experience-dependent modification of courtship behavior, and treatment with the same mG1uR antagonists or lithium rescues these memory defects. These findings implicate enhanced mGluR signaling as a contributing cause of the cognitive, as well as some of the behavioral and neuronal phenotypes, observed in the Drosophila Fragile X model. They also raise the possibility that compounds having similar effects on metabotropic glutamate receptors may ameliorate cognitive and behavioral defects observed in Fragile X patients.;The overriding clinical manifestation of Fragile X syndrome is mild to severe cognitive impairment. Age-dependent cognitive decline has been demonstrated as well, although it has not been 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 with this model in young adult flies 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. Furthermore, we show that treatment with mGluR antagonists or lithium can continue to restore naive courtship and memory in aged flies. These results indicate that the Drosophila model recapitulates the age-dependent cognitive decline observed in humans, and verify a role of dfmr1 in neuronal physiology. Furthermore, this suggests that misregulation of mGluR activity may be causative of this age-dependent decline and raises the possibility that mG1uRs may be a potential target for counteracting age-related memory impairment in Fragile X syndrome in humans.;Alzheimer's disease is the leading cause of neurodegeneration in the developed world. Although its genetic and environmental causes are generally not known, familial forms of the disease have been found to be due to mutations in a single copy of the Presenilin and Amyloid Precursor Protein genes. We have developed a Drosophila model for Alzheimer's disease that is based on haploinsufficiency for the Drosophila presenilin (psn) gene. Utilizing this model, young psn heterozygous (psn-het) flies display normal learning during training, immediate recall, and short-term memory in a conditioned courtship paradigm. However, with old age these flies display impairments in learning during training and short-term memory, whereas no deficits are seen in control flies. Treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium during the aging process prevented the onset of these deficits in psn heterozygotes, and treatment of aged flies reversed the age-dependent deficits in learning during training and short-term memory. These findings implicate enhanced mGluR signaling as an underlying cause of the age-dependent cognitive phenotypes observed in this Drosophila model of Alzheimer's disease. In addition, these studies raise the prospect that lithium-sensitive pathways, as well as metabotropic glutamate receptor signal transduction, may represent drug targets for amelioration of cognitive and behavioral defects observed in humans afflicted with Alzheimer's disease.