Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue.
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.
Choi
Catherine H
CH
Section of Molecular Cardiology and Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
McBride
Sean M J
SM
Schoenfeld
Brian P
BP
Liebelt
David A
DA
Ferreiro
David
D
Ferrick
Neal J
NJ
Hinchey
Paul
P
Kollaros
Maria
M
Rudominer
Rebecca L
RL
Terlizzi
Allison M
AM
Koenigsberg
Eric
E
Wang
Yan
Y
Sumida
Ai
A
Nguyen
Hanh T
HT
Bell
Aaron J
AJ
McDonald
Thomas V
TV
Jongens
Thomas A
TA
D000375:Aging / Q000523:psychology*; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D003072:Cognition Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D004330:Drosophila; D005260:Female; D007858:Learning; D008297:Male; D008568:Memory