The mushroom bodies are indicated in blue.
Like people, Drosophila have senior moments. Independent of age-related disorders, like Alzheimer's disease, aging impairs memory in many species, from insects to humans. The signaling molecules cAMP and cyclic AMP-dependent protein kinase (PKA) are important in hippocampal-dependent memory. Now Yamazaki et al. report mutations in PKA block age-related memory impairment (AMI) in a recent article in Nature Neuroscience.
In middle-aged Drosophila, AMI specifically affects middle-term memory, which occurs between one and three hours after associative learning. Researchers found a similar middle-term memory deficit in young Drosophila with mutations in the amnesiac gene, which encodes a neuropeptide precursor that localizes to neurons innervating the mushroom bodies, regions important in olfactory learning and memory in the insect brain. The authors hypothesized that AMI and amnesiac mutations affect the same cellular pathway.
They screened 54 Drosophila lines with mutations in mushroom body genes for altered AMI. One hour after learning to associate a scent with a shock, 1-day-old Drosophila avoided the shock-associated scent in a T maze. Consistent with AMI, 20-day-old Drosophila showed impaired performance relative to 1-day-old Drosophila. Drosophila heterozygous for DC0, which encodes the catalytic subunit of PKA, showed impaired AMI. Both 1- and 20-day-old DC0 mutant Drosophila performed similarly to 1-day-old wild-type Drosophila in the associative memory task. In even the oldest mutant Drosophila, the authors found no evidence of AMI.
DC0 expression in the mushroom bodies is important for AMI. The authors selectively rescued DC0 expression by mating DC0 mutant Drosophila expressing wild-type DC0 under the control of the yeast upstream activator sequence with several lines of Drosophila expressing the yeast transcription factor GAL4 in distinct brain regions. DC0 expression in mushroom but not ellipsoid or fan-shaped bodies rescued AMI in DC0 mutant Drosophila.
DC0 mutations rescued memory in amnesiac mutant Drosophila. Unlike amnesiac mutant Drosophila, Drosophila carrying mutations in both amnesiac and DC0 showed wild-type memory retention at 1 day of age. Unlike DC0 mutant Drosophila, Drosophila carrying mutations in both DC0 and amnesiac showed reduced performance in the associative memory task at 20 days of age, consistent with AMI.
The authors suppressed or advanced AMI by reducing or increasing PKA pathway signaling, respectively. AMI-deficient DC0 mutant Drosophila showed a 40% reduction in PKA activity relative to wild-type Drosophila. In the DC0 rescue experiment, one of the GAL4 drivers increased PKA activity by 26% relative to wild-type Drosophila, causing impaired memory at 1 day of age. Dunce encodes cAMP phosphodiesterase. Drosophila heterozygous for dunce showed AMI earlier than did wild-type Drosophila, with impaired performance in the associative memory task at 10 rather than 20 days of age. The authors suppressed AMI in wild-type Drosophila with a PKA competitive inhibitor.
Is PKA inhibition a viable treatment for AMI in people? In mice, increasing cAMP suppresses age-related impairment of hippocampal-dependent memory. These conflicting data suggest that different types of memory may require different levels of PKA activation. Alternatively, acute PKA activation may be beneficial, and chronic PKA activation may be detrimental to memory in the aging brain, according to the authors.