Maintenance of memory by negative feedback of synaptic protein elimination: modeling KIBRA–PKMζ dynamics in LTP
- Harel Z. Shouval1,2,
- Changchi Hsieh3,
- Rafael E. Flores-Obando3,
- David A. Cano4,
- Tara E. Tracy5 and
- Todd C. Sacktor3,6
- 1Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, Texas 77030, USA
- 2Department of Electrical and Computer Engineering, Rice University, Houston, Texas 77005, USA
- 3Department of Physiology and Pharmacology, State University of New York Downstate Health Sciences University, Brooklyn, New York 11203, USA
- 4School of Medicine, State University of New York Downstate Health Sciences University, Brooklyn, New York 11203, USA
- 5Buck Institute for Research on Aging, Novato, California 94945, USA
- 6Department of Neurology and Anesthesiology, State University of New York Downstate Health Sciences University, Brooklyn, New York 11203, USA
- Corresponding author: harel.shouval{at}uth.tmc.edu
Abstract
Long-term activity-dependent modifications of synaptic strength are a cellular substrate of learning and memory, but how long-lasting memory could be based on synaptic proteins that rapidly degrade and diffuse is unknown. Most current theories depend on molecular positive-feedback loops. Recent experiments, however, reveal that interactions between kidney brain protein (KIBRA) and PKMζ downregulate the proteins’ degradation and maintains late-phase long-term synaptic plasticity (LTP) and long-term memory, motivating an alternative model based on negative feedback at the level of protein elimination. Here we compare positive- and negative-feedback models generally and explore biophysical models based specifically on KIBRA–PKMζ interaction. The biophysical theory predicts LTP/memory maintenance by complexes of cooperative KIBRA–PKMζ heteromers.
Footnotes
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[Supplemental material is available for this article.]
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Article is online at http://www.learnmem.org/cgi/doi/10.1101/lm.054077.124.
- Received October 29, 2024.
- Accepted August 27, 2025.
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