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A Key to Long Term Memory Discovered

Summary: Brandeis researchers shed light on the role CaMKII plays in long-term memory creation and retention.

Source: Brandeis University.

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 results were published on September 27 in the online edition of Neuron.

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.

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 Alzheimer’s 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.

“Just like it’s unimaginable that we could understand cells if we didn’t understand DNA, it’s unimaginable that you can understand memory if you don’t know what molecule stores it,” Lisman says.

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.

Once the enzymes turn off, one would expect the memories to go with them. “This became a holy grail in neuroscience,” Lisman says. “How can a molecule in your brain serve as a memory? How does Nature accomplish this?”

Starting in the mid-1980s, Lisman began suspecting that the enzyme CaMKII could be the solution to this conundrum.

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, Lisman reasoned, 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,” Lisman says, “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.

Lisman kept plugging away at his research on CaMKII until 2009, when it began to look like he’d been all wrong. Researchers at SUNY Downstate Medical Center claimed to show that another kinase enzyme called PKMzeta was the molecule that stored memories. It garnered international attention.

Image shows a brain.

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. NeuroscienceNews.com image is in the public domain.

Lisman didn’t give up, though, and over the next several years, further studies cast doubt on the SUNY Downstate team’s findings.

To prove he was right, Lisman performed the same set of experiments with CaMKII as the SUNY Downstate group had with PKMzeta. He and his team placed a rat on a rotating platform. Every time the animal passed a designated location it got a small shock. Eventually the animal learned to avoid the shock zone by running in the opposite direction.

Lisman and his team then turned off the CaMKII molecules inside the rodent’s brain. The rat ceased getting off the platform to avoid the shock. The animal’s memory of the location of the shock zone had been erased.

In the model Lisman has developed, the chemical reactions caused by CaMKII work to strengthen the synaptic connections between neurons. Eventually those connections become permanent, creating a chain of neurons and synapses bonded to each other for good. It’s that chain that becomes a long-term memory.

About this neuroscience research article

The coauthors on the Neuron paper are Somdeb Banerjee, Chris Kim, Megan Leubner, Casey Lamar, Pooja Gupta and Bomsol Lee, all of Brandeis, and Rachael Neve, of Massachusetts General Hospital.

Source: Lawrence Goodman- Brandeis University
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “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

Cite This NeuroscienceNews.com Article
Brandeis University “A Key to Long Term Memory Discovered.” NeuroscienceNews. NeuroscienceNews, 28 September 2017.
<http://neurosciencenews.com/camkii-long-term-memory-7608/>.
Brandeis University (2017, September 28). A Key to Long Term Memory Discovered. NeuroscienceNews. Retrieved September 28, 2017 from http://neurosciencenews.com/camkii-long-term-memory-7608/
Brandeis University “A Key to Long Term Memory Discovered.” http://neurosciencenews.com/camkii-long-term-memory-7608/ (accessed September 28, 2017).

Abstract

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

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. We 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, we 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.

“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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