Sex- and experience-dependent regulation of synaptic protein turnover
7 affiliations
- 1Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine
- 2Johns Hopkins School of Medicine
- 3Department of Neuroscience, Tufts University School of Medicine
- 4Tufts University
- 5Department of Laboratory Medicine and Pathology, Mayo Clinic
- 6Mayo Clinic
- 7Center for Individualized Medicine, Mayo Clinic
Abstract
Synaptic transmission can be tuned through plasticity mechanisms that regulate synaptic strength, structure, and number. In vivo measurements demonstrate remarkable spine dynamics, with subsets of synapses persisting for months. This correlates with the longevity of certain memories, which can persist for an organism's lifetime. The molecular basis supporting the long-term stability of specific synapses and the long-term durability of memories remains unknown. At the protein level, most proteins persist for a relatively short amount of time before they are degraded and replaced with new molecules. However, recent work has identified a population of proteins, including those present at the synapse, that are exceptionally long-lived. It has been speculated that long-lived proteins (LLPs) could contribute to long-term synapse stability, function, and memory. Here, we used stable isotope labeling in mammals to first identify LLPs in the post synaptic density (PSD) of the hippocampus and subsequently determine if protein turnover rates varied by sex or following learning. We identified synaptic LLPs and found that both sex and experience can regulate synaptic protein turnover rates. We identified sex-dependent changes in protein turnover rates in autism spectrum disorder risk genes, including increased stability of Gabrg2, a GABA-A receptor subunit, in male mice. Furthermore, we observed stabilization of a subset of PSD proteins, such as Shank3, following contextual fear conditioning. We propose that sex- and experience-dependent changes in protein turnover rates could help explain sex-differences in psychiatric risk and aid our understanding of the molecular mechanisms that support learning and memory.
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BibTeX
@article{heo2026experiencedependent,
title = {{Sex- and experience-dependent regulation of synaptic protein turnover}},
author = {Seok Heo and Shiyu Zhang and Dong‐Gi Mun and Akhilesh Pandey and Alexei M. Bygrave and Richard L. Huganir},
journal = {Proceedings of the National Academy of Sciences},
year = {2026},
month = jul,
doi = {10.1073/pnas.2602111123},
url = {https://doi.org/10.1073/pnas.2602111123},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Sex- and experience-dependent regulation of synaptic protein turnover
AU - Seok Heo
AU - Shiyu Zhang
AU - Dong‐Gi Mun
AU - Akhilesh Pandey
AU - Alexei M. Bygrave
AU - Richard L. Huganir
PY - 2026
DA - 2026/07/07
JO - Proceedings of the National Academy of Sciences
DO - 10.1073/pnas.2602111123
UR - https://doi.org/10.1073/pnas.2602111123
AB - Synaptic transmission can be tuned through plasticity mechanisms that regulate synaptic strength, structure, and number. In vivo measurements demonstrate remarkable spine dynamics, with subsets of synapses persisting for months. This correlates with the longevity of certain memories, which can persist for an organism's lifetime. The molecular basis supporting the long-term stability of specific synapses and the long-term durability of memories remains unknown. At the protein level, most proteins persist for a relatively short amount of time before they are degraded and replaced with new molecules. However, recent work has identified a population of proteins, including those present at the synapse, that are exceptionally long-lived. It has been speculated that long-lived proteins (LLPs) could contribute to long-term synapse stability, function, and memory. Here, we used stable isotope labeling in mammals to first identify LLPs in the post synaptic density (PSD) of the hippocampus and subsequently determine if protein turnover rates varied by sex or following learning. We identified synaptic LLPs and found that both sex and experience can regulate synaptic protein turnover rates. We identified sex-dependent changes in protein turnover rates in autism spectrum disorder risk genes, including increased stability of Gabrg2, a GABA-A receptor subunit, in male mice. Furthermore, we observed stabilization of a subset of PSD proteins, such as Shank3, following contextual fear conditioning. We propose that sex- and experience-dependent changes in protein turnover rates could help explain sex-differences in psychiatric risk and aid our understanding of the molecular mechanisms that support learning and memory.
SN - 0027-8424
SN - 1091-6490
ER -