One question long plagued memory researcher Andr Fenton: How can memories last for years when a protein essential to maintaining them, called memory protein kinase Mzeta (PKMzeta), lasts for just days?
The answer, Fenton now says, may lie in PKMzetas interaction with another protein, called postsynaptic kidney and brain expressed adaptor protein (KIBRA). Complexes of the two molecules maintain memories in mice for at least one month, according to a new study co-led by Fenton, professor of neural science at New York University.
The bond between the two proteins protects each of them, Fenton says, from normal degradation in the cell.
KIBRA preferentially gloms onto potentiated synapses, the study shows. And it may help PKMzeta stick there, too, where the kinase acts as a molecular switch to help memories persist, Fenton says.
As Theseus Ship was sustained for generations by continually replacing worn planks with new timbers, long-term memory can be maintained by continual exchange of potentiating molecules at activated synapses, Fenton and his colleagues write in their paper, which was published last month in Science Advances.
Before this study, the PKMzeta mystery had two missing puzzle pieces, says Justin OHare, assistant professor of pharmacology at the University of Colorado Denver, who was not involved in the study.
One was how PKMzeta identifies potentiated synapses, part of the cellular mechanism underlying memory formation. The second was how memories persist despite the short lifetime of each PKMzeta molecule. This study essentially proposes KIBRA as a solution to both of thoseand the experiments themselves are pretty convincing and thorough. They do everything multiple ways.
P
The controversy, Fenton says, forced his team to look for another molecule that might be involved in long-term potentiation. They focused on KIBRA because the scaffolding protein is found in neurons and has been shown to interact with similar kinases in the sea slug.
In a common benchtop experiment of memory persistence, electrical stimulation of the CA3 region in mouse hippocampal slices induced complexes of KIBRA and PKMzeta to form in the synapses of the downstream CA1 stratum radiatum region, Fentons team found, confirming their suspicions.
Not only did [KIBRA and PKMzeta] interact, but they interacted in the right places for storing a memory or maintaining [long-term potentiation], Fenton says.
The excitatory postsynaptic potentials, a proxy for long-term potentiation, across CA1 neurons in the slices remained high three hours after stimulation, the researchers found, but then dipped back down to baseline after treatment with two moleculeszeta-stat and K-ZAPthat block the interaction between KIBRA and PKMzeta.
The two inhibitors also caused wildtype mice to forget their training in two different foot-shock experiments when administered either three days or one montha time frame longer than the kinases typical turnoverafter the animals had learned the task.
This result suggests that the KIBRA-PKMzeta complex is crucial for long-term potentiation and for memory maintenance, Fenton says.
E
That ruled out the possibility that other factorssuch as off-target effects of the two inhibitory moleculescaused the depotentiation or memory erasure in the mice. But it raised another question, Fenton says: So if PKMzeta is so important, and you delete it and you have normal memory and you have normal [long-term potentiation], like, what gives?
Another kinase, PKCiota/lambda, may step in and bind to KIBRA when PKMzeta is not around, Fenton says. Past work by Fenton and his colleagues has shown that PKCiota/lambda binds to KIBRA at a 10-fold lower rate than PKMzeta does.
This weaker interaction might explain why PKMzeta-null mice did maintain memories, but the memory is not as good, Fenton says. For example, in one experiment type, the PKMzeta-null mice re-enter an area where they previously received a mild foot shock more quickly than do their wildtype peers that did not receive the inhibitory molecules,but more slowly than the wildtype mice that received inhibitors,the study showed.
This result answers a question about another inhibitory molecule, the zeta inhibitor protein. ZIP, a 2020 study showed, interrupts long-term potentiation in mice that lack PKMzeta, indicating that memory relies on a completely different mechanism of action than PKMzeta, says Rami Yaka, professor of psychopharmacology at the Hebrew University of Jerusalem, who led the 2020 work but was not involved in the current study.
But ZIP is known to broadly target both PKMzeta and PKCiota/lambda, Fenton says. The inhibitors in the current study were specific to PKMzeta and so did not affect PKCiota/lambda.
There needed to be an explanation for why knocking out PKMzeta allowed memories to persist or [long-term potentiation] to persist, Fenton says.
How KIBRA becomes primed to capture PKMzeta and how KIBRA is attracted to the potentiated synapses remain open questions, says study investigator Panayiotis Tsokas, assistant professor in anesthesiology, physiology and pharmacology at SUNY Downstate Health Sciences University.
The answer might lie in calcium signaling in NMDA channels, which Tsokas says the team is exploring next.
Excerpt from:
Persistent protein pairing enables memories to last - The Transmitter: Neuroscience News and Perspectives
- Neuroscience Says Music Is an Emotion Regulation Machine. Heres What to Play for Happiness, Productivity, or Deep Thinking - Inc.com - April 19th, 2025 [April 19th, 2025]
- Early Maternal Affection Shapes Key Personality Traits for Life - Neuroscience News - April 19th, 2025 [April 19th, 2025]
- Elons new neuroscience major highlighted by Greensboro News & Record - Elon University - April 19th, 2025 [April 19th, 2025]
- Brain Blast event at St. Lawrence University teaches local students neuroscience - North Country Now - April 19th, 2025 [April 19th, 2025]
- AI Reveals What Keeps People Committed to Exercise - Neuroscience News - April 19th, 2025 [April 19th, 2025]
- The "Holy Grail" of Neuroscience? Researchers Create Stunningly Accurate Digital Twin of the Brain - The Debrief - April 19th, 2025 [April 19th, 2025]
- Annenberg School Vice Dean Emily Falk publishes book on the neuroscience of decision-making - The Daily Pennsylvanian - April 19th, 2025 [April 19th, 2025]
- Music-Induced Chills Trigger Natural Opioids in the Brain - Neuroscience News - April 19th, 2025 [April 19th, 2025]
- What We Value: The Neuroscience of Choice and Change - think.kera.org - April 19th, 2025 [April 19th, 2025]
- Kile takes top neuroscience post at Sutter Health as system pushes to align care, expand trials - The Business Journals - April 19th, 2025 [April 19th, 2025]
- A Grain of Brain, 523 Million Synapses, and the Most Complicated Neuroscience Experiment Ever Attempted - SciTechDaily - April 19th, 2025 [April 19th, 2025]
- Mild Brain Stimulation Alters Decision-Making Speed and Flexibility - Neuroscience News - April 19th, 2025 [April 19th, 2025]
- Cannabis studies were informing fundamental neuroscience in the 1970s - Nature - April 10th, 2025 [April 10th, 2025]
- To make a meaningful contribution to neuroscience, fMRI must break out of its silo - The Transmitter - April 10th, 2025 [April 10th, 2025]
- Steve Jobss Unexpected Secret to Being More Creative (Backed by Neuroscience) - Inc.com - April 10th, 2025 [April 10th, 2025]
- Challenging Decades of Neuroscience: Brain Cells Are More Plastic Than Previously Thought - SciTechDaily - April 10th, 2025 [April 10th, 2025]
- Q&A: Lundbecks head of R&D on letting biology speak in neuroscience - Endpoints News - April 10th, 2025 [April 10th, 2025]
- Why it's hard to study the neuroscience of psychedelics : Short Wave - NPR - April 10th, 2025 [April 10th, 2025]
- Fear Sync: How Males and Females Respond to Stress Together - Neuroscience News - April 10th, 2025 [April 10th, 2025]
- Chemotherapy Disrupts Brain Connectivity - Neuroscience News - April 10th, 2025 [April 10th, 2025]
- Newly awarded NIH grants for neuroscience lag 77 percent behind previous nine-year average - The Transmitter - April 10th, 2025 [April 10th, 2025]
- Wittstein interviewed by The Times News about new neuroscience major - Elon University - April 10th, 2025 [April 10th, 2025]
- Alto Neuroscience initiated with a Buy at H.C. Wainwright - Yahoo Finance - April 10th, 2025 [April 10th, 2025]
- New map of brain hailed as watershed for neuroscience - The Times - April 10th, 2025 [April 10th, 2025]
- GSK Ramps Up Neuroscience Investment With ABL Brain Shuttle Deal - insights.citeline.com - April 10th, 2025 [April 10th, 2025]
- ADHD and Music: Why Background Beats May Boost Study Focus - Neuroscience News - April 10th, 2025 [April 10th, 2025]
- Brains Rewire Themselves to Survive Deadly Infection - Neuroscience News - April 10th, 2025 [April 10th, 2025]
- AbbVie Hold Rating: Balancing Strong Immunology Growth with Challenges in Aesthetics, Neuroscience, and Oncology - TipRanks - April 10th, 2025 [April 10th, 2025]
- Want to Feel Better and Be More Mindful? Neuroscience Says This Habit Might Be Holding You Back - Inc.com - April 10th, 2025 [April 10th, 2025]
- How One Bad Meal Rewires the Brain to Avoid That Food Forever - Neuroscience News - April 10th, 2025 [April 10th, 2025]
- Marcus Neuroscience Institute to Host Brain and Spine Symposium - South Florida Hospital News - March 30th, 2025 [March 30th, 2025]
- Elon University to launch neuroscience major in fall 2025 - Today at Elon - March 30th, 2025 [March 30th, 2025]
- The brains stalwart sentinels express an unexpected gene - The Transmitter: Neuroscience News and Perspectives - March 30th, 2025 [March 30th, 2025]
- Video catches microglia in the act of synaptic pruning - The Transmitter: Neuroscience News and Perspectives - March 30th, 2025 [March 30th, 2025]
- Null and Noteworthy: Reexamining registered reports - The Transmitter: Neuroscience News and Perspectives - March 30th, 2025 [March 30th, 2025]
- Accepting the bitter lesson and embracing the brains complexity - The Transmitter: Neuroscience News and Perspectives - March 30th, 2025 [March 30th, 2025]
- NIH neurodevelopmental assessment system now available as iPad app - The Transmitter: Neuroscience News and Perspectives - March 30th, 2025 [March 30th, 2025]
- Stronger Bonds Before Birth Shape Healthier Mother-Child Futures - Neuroscience News - March 30th, 2025 [March 30th, 2025]
- How Emotionally Intelligent People Learn to Control Their Inner Voice, Backed by Neuroscience - Inc. - March 30th, 2025 [March 30th, 2025]
- Gabriele Scheler reflects on the interplay between language, thought and AI - The Transmitter: Neuroscience News and Perspectives - March 30th, 2025 [March 30th, 2025]
- Worlds first crowd-sourced neuroscience study aims to understand how our brains predict the future - EurekAlert - March 15th, 2025 [March 15th, 2025]
- Rewriting Neuroscience: Possible Foundations of Human Intelligence Observed for the First Time - SciTechDaily - March 15th, 2025 [March 15th, 2025]
- Calculating neurosciences carbon cost: Q&A with Stefan Pulver and William Smith - The Transmitter: Neuroscience News and Perspectives - March 15th, 2025 [March 15th, 2025]
- The future of neuroscience research at U.S. minority-serving institutions is in danger - The Transmitter: Neuroscience News and Perspectives - March 15th, 2025 [March 15th, 2025]
- Dopamine and social media: Why you cant stop scrolling, according to neuroscience - PsyPost - March 15th, 2025 [March 15th, 2025]
- Neuroscience Discovered a Clever Trick for Squeezing More Joy Out of Everyday Pleasures - Inc. - March 15th, 2025 [March 15th, 2025]
- The limits of neuroscience - The Transmitter: Neuroscience News and Perspectives - March 15th, 2025 [March 15th, 2025]
- BPOM Explains The Benefits Of Fasting From The Health And Neuroscience Side - VOI English - March 15th, 2025 [March 15th, 2025]
- How tiny tardigrades could help tackle systems neuroscience questions - The Transmitter: Neuroscience News and Perspectives - March 15th, 2025 [March 15th, 2025]
- Alison Preston explains how our brains form mental frameworks for interpreting the world - The Transmitter: Neuroscience News and Perspectives - March 15th, 2025 [March 15th, 2025]
- The Mystical Mind Meets Neuroscience: Seeking the Roots of Consciousness - Next Big Idea Club Magazine - March 15th, 2025 [March 15th, 2025]
- Myosin Therapeutics Closes Second Seed Round to Advance Clinical Trials for Innovative Cancer and Neuroscience Therapies - PR Newswire - March 5th, 2025 [March 5th, 2025]
- Neuroscience Ph.D. programs adjust admissions in response to U.S. funding uncertainty - The Transmitter: Neuroscience News and Perspectives - March 5th, 2025 [March 5th, 2025]
- New tools help make neuroimaging accessible to more researchers - The Transmitter: Neuroscience News and Perspectives - March 5th, 2025 [March 5th, 2025]
- Future Thinking Training Reduces Impulsivity - Neuroscience News - March 5th, 2025 [March 5th, 2025]
- Null and Noteworthy, relaunched: Probing a schizophrenia biomarker - The Transmitter: Neuroscience News and Perspectives - March 5th, 2025 [March 5th, 2025]
- How to communicate the value of curiosity-driven research - The Transmitter: Neuroscience News and Perspectives - March 5th, 2025 [March 5th, 2025]
- Cognitive neuroscience approach to explore the impact of wind turbine noise on various mental functions - Nature.com - March 5th, 2025 [March 5th, 2025]
- Football on the Brain: Helping coaches embed neuroscience knowledge - Training Ground Guru - March 5th, 2025 [March 5th, 2025]
- Taking Control: Using Neuroscience to Build Better Lives - theLoop - March 5th, 2025 [March 5th, 2025]
- Creating a pipeline of talent to feed the growth of Neuroscience: Lessons from Ghana - Myjoyonline - March 5th, 2025 [March 5th, 2025]
- Exclusive: NIH appears to archive policy requiring female animals in studies - The Transmitter: Neuroscience News and Perspectives - February 25th, 2025 [February 25th, 2025]
- Roll On Down The Highway 2025 Tour coming to Neuroscience Group Field - WeAreGreenBay.com - February 25th, 2025 [February 25th, 2025]
- STEM organizations host Neuroscience Outreach Fair for local K-12 students - University of Virginia The Cavalier Daily - February 25th, 2025 [February 25th, 2025]
- Adapt or die: Safeguarding the future of diversity and inclusion funding in neuroscience - The Transmitter: Neuroscience News and Perspectives - February 25th, 2025 [February 25th, 2025]
- The last two-author neuroscience paper? - The Transmitter: Neuroscience News and Perspectives - February 25th, 2025 [February 25th, 2025]
- Gate Neurosciences Strengthens Focus on the Synapse as a Therapeutic Target with Acquisition of Boost Neuroscience - Business Wire - February 25th, 2025 [February 25th, 2025]
- Why Firefly Neuroscience, Inc. (AIFF) Is Soaring This Year So Far - Yahoo Finance - February 25th, 2025 [February 25th, 2025]
- Breaking the barrier between theorists and experimentalists - The Transmitter: Neuroscience News and Perspectives - February 25th, 2025 [February 25th, 2025]
- Preserving Brain Health and Advancing Neuroscience - University of Miami - February 25th, 2025 [February 25th, 2025]
- Science must step away from nationally managed infrastructure - The Transmitter: Neuroscience News and Perspectives - February 25th, 2025 [February 25th, 2025]
- Repurposed Blood Pressure Drug May Treat ADHD - Neuroscience News - February 25th, 2025 [February 25th, 2025]
- How to teach students about science funding - The Transmitter: Neuroscience News and Perspectives - February 25th, 2025 [February 25th, 2025]
- Reflecting on 2024: Advancing Neuroscience Research to Improve Neurological Health - National Institute of Neurological Disorders and Stroke - February 25th, 2025 [February 25th, 2025]
- Brains Hidden Circuitry for Risk and Reward Uncovered - Neuroscience News - February 25th, 2025 [February 25th, 2025]
- Why We Keep Exploring Even After Learning the Best Strategy - Neuroscience News - February 25th, 2025 [February 25th, 2025]
- Unlocking Cellular Youth: The Protein That Reverses Aging - Neuroscience News - February 25th, 2025 [February 25th, 2025]
- This paper changed my Life: Bill Newsome reflects on a quadrilogy of classic visual perception studies - The Transmitter: Neuroscience News and... - February 25th, 2025 [February 25th, 2025]
- Roundup: The false association between vaccines and autism - The Transmitter: Neuroscience News and Perspectives - February 3rd, 2025 [February 3rd, 2025]
- Static pay, shrinking prospects fuel neuroscience postdoc decline - The Transmitter: Neuroscience News and Perspectives - February 3rd, 2025 [February 3rd, 2025]