How does our brain form long-term memories?

Researchers have discovered a biological basis for the storage of long-term memories, centered around a molecule called KIBRA.

This study, published in the journal Science Advances, reveals how KIBRA acts as a “glue” to solidify memory formation by interacting with other crucial molecules like protein kinase Mzeta (PKMzeta).

Holding onto memories for the long term 

“Previous efforts to understand how molecules store long-term memory focused on the individual actions of single molecules,” said André Fenton, a professor of neural science at New York University and one of the study’s principal investigators. “Our study shows how they work together to ensure perpetual memory storage.”

“A firmer understanding of how we keep our memories will help guide efforts to illuminate and address memory-related afflictions in the future,” added senior author Todd Sacktor, a professor at SUNY Downstate Health Sciences University.

Stability of memories over time

While neurons store information as strong and weak synapses, the instability of molecules in synapses raises questions about the stability of memories over time. 

The study used laboratory mice to focus on KIBRA’s role in memory, identifying it as the key component that ensures memory persistence. KIBRA acts as a “persistent synaptic tag,” binding to strong synapses and PKMzeta, while avoiding weak ones. This allows PKMzeta to strengthen specific synapses continually.

“During memory formation, the synapses involved in the formation are activated – and KIBRA is selectively positioned in these synapses,” Sacktor explained. 

“PKMzeta then attaches to the KIBRA-synaptic-tag and keeps those synapses strong. This allows the synapses to stick to newly made KIBRA, attracting more newly made PKMzeta.”

Enhancing weak or faded memories 

The experiments demonstrated that disrupting the KIBRA-PKMzeta bond can erase old memories, while increasing PKMzeta can enhance weak or faded memories. This persistent synaptic tagging explains the enhanced memory effect observed in previous studies.

“The persistent synaptic tagging mechanism for the first time explains these results that are clinically relevant to neurological and psychiatric disorders of memory,” Fenton said.

Proteins are replaced to hold long-term memories 

The research supports a concept introduced by Francis Crick in 1984, akin to the philosophical idea of Theseus’s Ship, where new planks replace old ones to maintain the ship.

“The persistent synaptic tagging mechanism we found is analogous to how new planks replace old planks to maintain Theseus’s Ship for generations, and allows memories to last for years even as the proteins maintaining the memory are replaced,” said Sacktor.

“Francis Crick intuited this Theseus’s Ship mechanism, even predicting the role for a protein kinase. But it took 40 years to discover that the components are KIBRA and PKMzeta and to work out the mechanism of their interaction.”

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