A remarkable array of cellular mechanisms is engaged when we store information in our memory, whether for near-term or long-term retrieval. One of the great mysteries of brain science is the fact that some memories are retained intact for decades, even though the proteins in the brain that accomplish the work of memory are short-lived, many extant for only a few days before they are replaced by fresh proteins.

A team of researchers led by BBRF 2017 Young Investigator Kevin Beier, Ph.D., of the University of California, Irvine, has reported important new findings about the mechanisms of memory. As they explain in the journal Nature, the team arrived at new insights in experiments that began with a peptide, or protein fragment, called ZIP (zeta inhibitory peptide).

They knew that when injected into the mouse brain, ZIP can interfere with an animal’s ability to retain a memory—what scientists call memory maintenance. One commonly studied mechanism thought to underlie memories is long-term potentiation (LTP), which is the persistent strengthening of particular synapses, the tiny spaces across which neighboring neurons communicate. Strengthening of a group (or groups) of synapses is part of the process through which a memory is registered in the brain. The new findings reveal a previously unknown synaptic mechanism by which memories are maintained or lost, and thus have relevance for ongoing efforts to find novel treatments for such conditions as dementia, traumatic brain injury, and post-traumatic stress disorder (PTSD).

How and why does ZIP interfere with the maintenance of a memory? Dr. Beier and colleagues noted that 6 of the 13 amino-acid building blocks of the peptide carry a positive charge, making ZIP “cationic,” i.e., a carrier of a positive electric charge. This is important because cationic substances, including peptides, are known to act at the membrane of cells to induce endocytosis. Endocytosis is a process in which a tiny portion of the outer membrane of a cell curls into a cup-shaped depression and envelops a substance either sitting on the membrane or floating in the space just outside the cell. It encloses this substance, forming a “vesicle,” and brings it into the cell’s interior, often for elimination or reprocessing.

What does this have to do with memory? The research reported by the team confirmed their hypothesis that ZIP’s presence can cause endocytosis to occur at the membrane of nerve cells in the brain. In this case, the cell forms a vesicle that swallows up AMPA receptors, which are docking ports for glutamate, the brain’s most important excitatory neurotransmitter. The AMPA receptor is a large multi-part protein structure that projects through the cell membrane into the space outside it, to capture glutamate molecules. ZIP-induced endocytosis, by swallowing up AMPA receptors at the nerve cell membrane—and, experiments showed, in particular, tiny clusters of receptors that have most recently formed—interferes with the memory retention process.

Not only ZIP, but other positively-charged peptides could similarly interfere with memory retention, via the same mechanism, experiments indicated. Behavioral experiments in mice revealed that the loss of specific memories following injection into the brain of a cationic peptide like ZIP was permanent: affected memories did not return with the passage of time. On the other hand, the loss of memory did not cause long-term damage to portions of the brain where these memories reside (in this case, parts of the amygdala and hippocampus). Different kinds of memories are stored in each region. After cation-induced memory loss, mice could re-learn, for example, to associate a sound with a soon-to-be-felt mild shock; or to associate a particular place with obtaining an addictive drug.

Other experiments revealed how a positively charged or cationic peptide like ZIP induces endocytosis. Cationic peptides that can cause memory loss, the team found, need to stimulate a particular form of endocytosis mediated by a protein called endophilin-A2. Again, this led to a broader discovery: agents that trigger this form of endocytosis are necessary and sufficient in themselves to disrupt memory.

This finding sheds light on how the new research might help inform development of future treatments for brain conditions affecting memory—those in which one would want to halt memory deterioration, like that which occurs in traumatic brain injury, or perhaps in PTSD, in which memory of a traumatic event impairs a person’s ability to function.

In a mouse model of traumatic brain injury, the team found that treatment with an existing hypertension drug, a diuretic called amiloride, prevented trauma-induced amnesia. This suggested to them that in their research on cationic peptides and why, via endocytosis, they cause memory loss, they had uncovered “a general mechanism of naturally occurring memory loss in neurological disease.”

Among other things, the findings suggest the importance of selectively targeting new clusters of AMPA receptors in efforts to modulate memory—whether to prevent or slow memory loss, or to ameliorate neurological conditions that impair normal memory function.

The research team also included Jason Aoto, Ph.D., a 2016 BBRF Young Investigator.