The Drosophila DCO mutation suppresses age-related memory impairment without affecting lifespan.
The study of age-related memory impairment (AMI) has been hindered by a lack of AMI-specific mutants. In a screen for such mutants in Drosophila melanogaster, we found that heterozygous mutations of DCO (DCO/+), which encodes the major catalytic subunit of cAMP-dependent protein kinase (PKA), delay AMI more than twofold without affecting lifespan or memory at early ages. AMI is restored when a DCO transgene is expressed in mushroom bodies, structures important for olfactory memory formation. Furthermore, increasing cAMP and PKA activity in mushroom bodies causes premature AMI, whereas reducing activity suppresses AMI. In Drosophila AMI consists of a specific reduction in memory dependent on the amnesiac (amn) gene. amn encodes putative neuropeptides that have been proposed to regulate cAMP levels in mushroom bodies. Notably, both the memory and AMI defects of amn mutants are restored in amn;DCO/+ double mutants, suggesting that AMI is caused by an age-related disruption of amn-dependent memory via PKA activity in mushroom bodies.
Yamazaki
Daisuke
D
Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan.
Horiuchi
Junjiro
J
Nakagami
Yasuko
Y
Nagano
Shintaro
S
Tamura
Takuya
T
Saitoe
Minoru
M
D000375:Aging / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D048149:Casein Kinase 1 epsilon / Q000235:genetics*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D006727:Hormone Antagonists / Q000008:administration & dosage; D008569:Memory Disorders / Q000235:genetics* / Q000503:physiopathology*; D015735:Mifepristone / Q000008:administration & dosage; D024521:Mushroom Bodies / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D009812:Odorants; D016019:Survival Analysis; D013997:Time Factors
D029721:Drosophila Proteins; D006727:Hormone Antagonists; C113519:dco protein, Drosophila; D015735:Mifepristone; D000242:Cyclic AMP; D048149:Casein Kinase 1 epsilon; D017868:Cyclic AMP-Dependent Protein Kinases