Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue.
Publication/Presentation Date
6-1-2010
Abstract
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.
Volume
11
Issue
3
First Page
347
Last Page
362
ISSN
1573-6768
Published In/Presented At
Choi, C. H., McBride, S. M., Schoenfeld, B. P., Liebelt, D. A., Ferreiro, D., Ferrick, N. J., Hinchey, P., Kollaros, M., Rudominer, R. L., Terlizzi, A. M., Koenigsberg, E., Wang, Y., Sumida, A., Nguyen, H. T., Bell, A. J., McDonald, T. V., & Jongens, T. A. (2010). Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue. Biogerontology, 11(3), 347–362. https://doi.org/10.1007/s10522-009-9259-6
Disciplines
Medicine and Health Sciences
PubMedID
20039205
Department(s)
Department of Medicine
Document Type
Article