Unlocking memory’s mysteries

JUPITER, Fla.—Researchers at The Scripps Research Institute (TSRI) conducting a memory formation study at its Florida campus have identified a memory suppressor gene in brain cells of the common fruit fly, Drosophila, as well as the human counterparts to the fly gene.

Led by the chair of the TSRI Department of Neuroscience, Ron Davis, the team of scientists screened approximately 3,500 Drosophila genes and identified several dozen new memory suppressor genes that the brain has to help filter information and store only important parts.

The researchers screened the fruit fly genes by expressing an RNA interference that inhibits gene expression, so as to deactivate each of the 3,500 Drosophila genes and test each inactivated gene for its effect on memory. The test examined the flies’ memory of smells, which is the most widely studied form of memory typical of this model.

“As a result, we found more than three dozen [genes] that had an impact on memory—when they were inactivated, fly memory was enhanced,” says Davis. “We concluded that these genes constrain memory in the normal fly.”

The study was published April 14, 2016, in the journal Neuron.

The team was especially struck by one of the suppressor genes, DmSLC22A, identified in the screening process. The flies’ memory of smells was enhanced greatly when the researchers disabled this gene, while overexpression of the gene inhibited the same memory function.

“In the case of the DmSLC22A gene, we had a robust increase in memory—nearly twofold—when it was deactivated,” says Davis, the corresponding author of the study.

The DmSLC22A gene belongs to a family of plasma membrane transporters, which produce proteins that move molecules across cell walls. The TSRI study indicates that the DmSLC22A gene makes a protein involved in moving neurotransmitter molecules from the synaptic space between neurons back into the neurons. Under normal circumstances, the protein it makes removes the neurotransmitter acetylcholine from the synapse, helping to terminate the synaptic signal. When gene is disabled and the protein is missing, more acetylcholine persists in the synapse, leaving the synaptic signal stronger and more persistent, which leads to enhanced memory.

“DmSLC22A serves as a bottleneck in memory formation,” said research associate and co-first author Yunchao Gai in a media release about the study. “Considering the fact that plasma transporters are ideal pharmacological targets, drugs that inhibit this protein may provide a practical way to enhance memory in individuals with memory disorders.”

“The vast majority of drugs affect cell surface proteins, primarily because the drug doesn’t have to enter the cell to do its work; it’s simply easier to achieve an effect with a surface protein as the target,” says Davis.

Despite the obvious anatomical differences between common fruit flies and humans, the researchers are highly confident that their findings in Drosophila genes will translate to similar genes in mammals, including humans.

“Memory processes and the genes that make the brain proteins required for memory are evolutionarily conserved between mammals and fruit flies,” said research associate and the study’s other co-first author Ze Liu in a news release. “The majority of human cognitive disease-causing genes have the same functional genetic counterparts in flies.”

“The genetics between flies and humans are phenomenally conserved between flies and humans in terms of their structure and their function,” says Davis. “Flies have 15,000 genes while humans have around 23,000. In fact, there’s a greater than 90-percent chance that a fly gene will have a counterpart to one in humans. To a significant degree, the fly offers a system to tell us which genes are important for memory and learning in both species.”

Davis and his team have identified the human counterparts to the fly gene. “The complexity comes from the fact that while there is only one gene in the fly, there are at least four similar genes in humans,” says Davis. “We now have to figure out which of the four works in people.”

Once the human gene responsible for the memory suppression function identified in fruit flies is pinpointed, the next step for Davis and his team will be to duplicate their study in mice, an intermediate system between fruit flies and humans.

“Once we duplicate our study results in mouse models, we want to find and develop inhibitors that would work in that model,” says Davis.