The waiter takes your order without writing it down. You carry on a conversation without asking for explanations every few minutes. You’re able to punch in the digits of that telephone number you just heard.

Short-term memory enables us to do all these things and more. How does that happen on the molecular level? New research from Harvard Medical School has identified a calcium sensor important in this process.

Neuroscientists know that our brains form memories by changing the properties of brain cells and their connections, depending on the strength of the stimuli these cells receive. This malleability is called plasticity, and it occurs at the synaptic junctions where neurons connect.

Short-term memory involves an influx of calcium ions into cells on the “before” side of the synapse, or the presynaptic cell, which has just generated an electrical signal in response to a stimulus. These ions activate specific calcium sensors that in turn trigger the release of neurotransmitters from the presynaptic cell to the postsynaptic cell on the “after” side, producing an electrical signal whose strength can vary.  

Now HMS scientists have revealed an important player in this sequence of events crucial to synaptic plasticity and short-term memory. They have shown for the first time that an enzyme called protein kinase C (PKC) senses an increase in calcium, and as a result helps strengthen the connections between brain cells.

Pinpointing this sensor opens the door to a better understanding of how this increase in calcium strengthens the synapse that supports short-term memory.

“We have identified a pathway that we can then manipulate to understand how the nervous system uses plasticity to modify function,” said Diasynou Fioravante, the paper’s co-first author. Now assistant professor of neurobiology, physiology and behavior at the University of California, Davis, she led the experiments while working in the lab of Wade Regehr, HMS professor of neurobiology and the paper’s senior author.

“By knowing that PKC is the molecule that senses calcium, we can study the dynamics of PKC and understand how these correlate with the changes in synaptic connections that we see in short-term memory,” Fioravante said.

The findings appear in the journal eLife.

Fioravante, Regehr and their colleagues used tools from electrophysiology and genetics to show for the first time that PKC is required to boost the synaptic signal between neurons. Animals genetically engineered to lack PKC had weak synaptic connections, but those connections became stronger when the scientists delivered PKC to them via a viral infusion.

When the scientists mutated the amino acids in PKC, it didn’t respond to calcium, bolstering their evidence that PKC is in fact a sensor for presynaptic short-term plasticity.

Based on previous work about the related kinase PKC gamma, the scientists believe there is a PKC family of presynaptic calcium sensors. Future studies will further illuminate the richness of communication between neurons, Fioravante said.

One tantalizing question pertains to the relationship between short- and long-term memory, especially in disease.

“There is a hypothesis that without short-term memory, you cannot have long-term memory. The idea is you have to process the information first before you can remember it,” she said. “Now that we have a way to manipulate short-term memory, we can test if that is true or not.”

This work was supported by National Institutes of Health grants NS032405, K01DA029044, F30-DC013716-01 and T32 NS007484; a Howard Hughes Medical Institute Medical Research Fellow grant; and postdoctoral fellowship NWO 825.12.028 from the Netherlands Organization for Scientific Research.