Researchers shed light on long-term memory creation and retention.

A key to long-term memory discovered

After a 30-year quest, a Brandeis professor has discovered the molecule that stores long-term memories — it’s called calcium/calmodulin-dependent protein kinase, or CaMKII for short.

The discovery of the memory molecule resolves one of the oldest mysteries in neuroscience — how do our brains create and retain long-term memories?

The finding also opens up radically new avenues of brain research. One day, by targeting CaMKII, we may be able to erase the memories that underlie trauma or drug addiction. Though it would raise serious ethical issues, it might also allow us to change our pasts by wiping out recollections of unhappy experiences.

CaMKII has also been found to play a role in dementia disease. It’s never been clear if the illness deletes long-term memories or if they remain present, yet inaccessible to recall. A better understanding of CaMKII might resolve this.

A memory may feel abstract or immaterial, but it is actually a biochemical process taking place in the brain. It involves neurons communicating with each other via the “wires” or synapses connecting them.

The pathway an electrochemical signal follows as it continually travels from neuron to synapse to neuron constitutes a memory. Whenever you have that memory, the same pathway gets activated. And the more it’s activated, the more it becomes hardwired into the brain’s circuitry. Eventually, it becomes a long-term memory.

Activation also requires enzymes, molecules that set off chemical reactions. The problem is that these enzymes don’t exist for longer than a week. If a memory is to endure, it would seem that the enzymes would have to remain functioning for years or even decades.

How can a molecule in your brain serve as a memory?

When a CaMKII molecule stops working, it can be reactivated by another CaMKII. This means there are always lots of CaMKII molecules available to take the place of the CaMKII that’s stopped working. In theory,

Clusters of CaMKII could recruit replacement molecules without losing their overall function. This would mean the clusters would be, in effect, long-lasting even if their component molecules were constantly changing.

The amazing thing about CaMKII is that once you turn it on, it stays on more or less forever.

In this sense, CaMKII “stores” memory. It becomes the molecule whose permanence ensures the memory doesn’t fade. Despite numerous other biochemical changes in the brain, it retains a record of what it needs to do to make a memory endure.

Models have been developed showing the chemical reaction caused by CaMKII work to strengthen the synaptic connection between neurons. Eventually, those connections become permanent, creating a chin of neurons and synapses bounded each other for good. It’s that chain that becomes a long-term memory.

The pathway an electrochemical signal follows as it continually travels from neuron to synapse to neuron constitutes a memory. Whenever you have that memory, the same pathway gets activated. And the more it’s activated, the more it becomes hardwired into the brain’s circuitry. Eventually, it becomes a long-term memory.

Noteworthy

Highlights

• Dominant-negative CaMKII erases a hippocampal-dependent memory
• The abundant synaptic protein CaMKII is a memory storage molecule
• Activated CaMKII saturates synaptic weights and impairs memory
• CaMKII autophosphorlaytion suggests a simple mechanism for stable memory storage

Summary

The abundant synaptic protein CaMKII is necessary for long-term potentiation (LTP) and memory. However, whether CaMKII is required only during initial processes or whether it also mediates memory storage remains unclear.

The most direct test of a storage role is the erasure test. In this test, a putative memory molecule is inhibited after learning. The key prediction is that this should produce persistent memory erasure even after the inhibitory agent is removed.

Researchers conducted this test using transient viral (HSV) expression of dominant-negative CaMKII-alpha (K42M) in the hippocampus.

This produced persistent erasure of conditioned place avoidance. As an additional test, it was found that expression of activated CaMKII (T286D/T305A/T306A) impaired place avoidance, a result not expected if a process other than CaMKII stores memory.

Our behavioral results, taken together with prior experiments on LTP, strongly support a critical role of CaMKII in LTP maintenance and memory storage.

The more scientists unravel the complexities of the working brain, and the role played in dementia disease. This will allow us to design innovative implants that could store or even active memories for patients suffering from dementia.

Its never been clear if the illness deletes long-term memories or if they remain present, yet inaccessible to recall.

Acknowledgments & References

The breakthrough was achieved by the lab of John Lisman ’66, the Zalman Abraham Kekst Chair in Neuroscience. The paper’s first author is Tom Rossetti, a former undergraduate student of Lisman’s now at the Weill Cornell Medicine Graduate School of Medical Sciences. Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage” by Tom Rossetti, Somdeb Banerjee, Chris Kim, Megan Leubner, Casey Lamar, Pooja Gupta, Bomsol Lee, Rachael Neve, and John Lisman in Neuron. Published online September 27 2017 doi:10.1016/j.neuron.2017.09.010

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