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Cited by 5Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersMemory and Neural Mechanisms

Sex- and experience-dependent regulation of synaptic protein turnover

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Heo, Seok, Zhang, Shiyu, Mun, Dong-Gi, Pandey, Akhilesh, Bygrave, Alexei M., Huganir, Richard L.·2026·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2602111123PMC PMC13367811
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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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  • Stable spine dynamics, with subsets of synapses persisting for months.

    “They see stable spine dynamics, with subsets of synapses persisting for months.”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [24]

    The paper’s introductory text says that in vivo imaging has shown some synapses persist for months, citing an earlier study (reference 7). Its own Results examine synaptic protein turnover, not spine dynamics, so “They see” overstates what these authors observed. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The lifetimes of brain proteins vary widely.

    “Moreover, the lifetimes of brain proteins vary widely [22][23][24]”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [24]

  • A population of proteins, including those present at the synapse, are exceptionally long-lived.

    “Recent work has identified a population of proteins, including those present at the synapse that are exceptionally long-lived, and suggest sex and experiencedependent changes in the expression of some of these long-lived proteins.”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [24]

  • There are sex and experience-dependent changes in the expression of some of these long-lived proteins.

    “Recent work has identified a population of proteins, including those present at the synapse that are exceptionally long-lived, and suggest sex and experiencedependent changes in the expression of some of these long-lived proteins.”

    From A feature and not a bug: Replication failures can lead to new biology (2026) · cites this paper as [24]

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Research works printed but not linked: 40

  1. [2]W. Li, Turnover atlas of proteome and phosphoproteome across mouse tissues and brain regions. Cell 188, 2267– 2287.e21 (2025). 40118046 PMC12033170
  2. [3]E. F. Fornasiero, Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions. Nat. Commun. 9, 4230 (2018). 30315172 PMC6185916
  3. [4]S. Heo, Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover. Proc. Natl. Acad. Sci. U.S.A. 115, E3827– E3836 (2018). 29610302 PMC5910858
  4. [5]H. Zhang, Brain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice. Nat. Commun. 7, 11773 (2016). 27249678 PMC4895353
  5. [6]N. Yamashita, CRMP5 (collapsin response mediator protein 5) regulates dendritic development and synaptic plasticity in the cerebellar Purkinje cells. J. Neurosci. 31, 1773– 1779 (2011). 21289187 PMC6623753
  6. [7]J. T. Trachtenberg, Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788– 794 (2002). 12490942
  7. [8]U. Frey, R. G. Morris, Synaptic tagging: Implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci. 21, 181– 188 (1998). 9610879
  8. [9]A. R. Dörrbaum, L. Kochen, J. D. Langer, E. M. Schuman, Local and global influences on protein turnover in neurons and glia. Elife 7, e34202 (2018). 29914620 PMC6008053
  9. [10]R. Loomes, L. Hull, W. P. L. Mandy, What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. J. Am. Acad. Child Adolesc. Psychiatry 56, 466– 474 (2017). 28545751
  10. [11]J. R. Geiger, Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15, 193– 204 (1995). 7619522
  11. [12]C. Y. Zheng, R. S. Petralia, Y. X. Wang, B. Kachar, R. J. Wenthold, Sap102 is a highly mobile maguk in spines. J. Neurosci. 30, 4757– 4766 (2010). 20357126 PMC2874826
  12. [13]Y. Yang, Sex differences in clinically diagnosed psychiatric disorders over the lifespan: A nationwide register-based study in Sweden. Lancet Reg. Health Eur. 47, 101105 (2024). 39726722 PMC11670697
  13. [14]A. K. Bonkhoff, Sex differences in age-associated neurological diseases-A roadmap for reliable and high-yield research. Sci. Adv. 11, eadt9243 (2025). 40043111 PMC11881909
  14. [15]J. R. Geiger, J. Lübke, A. Roth, M. Frotscher, P. Jonas, Submillisecond AMPA receptor-mediated signaling at a principal neuron-interneuron synapse. Neuron 18, 1009– 1023 (1997). 9208867
  15. [16]K. A. Pelkey, Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron 85, 1257– 1272 (2015). 25754824 PMC4368480
  16. [17]J. B. Melander, Distinct in vivo dynamics of excitatory synapses onto cortical pyramidal neurons and parvalbumin-positive interneurons. Cell Rep. 37, 109972 (2021). 34758304 PMC8631347
  17. [18]E. Fernández, Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins. Mol. Syst. Biol. 5, 269 (2009). 19455133 PMC2694677
  18. [19]A. M. Bygrave, Btbd11 supports cell-type-specific synaptic function. Cell Rep. 42, 112591 (2023). 37261953 PMC10592477
  19. [20]D. F. Levey, Bi-ancestral depression GWAS in the Million Veteran Program and meta-analysis in >1.2 million individuals highlight new therapeutic directions. Nat. Neurosci. 24, 954– 963 (2021). 34045744 PMC8404304
  20. [21]N. A. Kimbrel, Identification of novel, replicable genetic risk loci for suicidal thoughts and behaviors among US military veterans. JAMA Psychiatry 80, 135– 145 (2023). 36515925 PMC9857322
  21. [22]C. M. Nievergelt, Genome-wide association analyses identify 95 risk loci and provide insights into the neurobiology of post-traumatic stress disorder. Nat. Genet. 56, 792– 808 (2024). 38637617 PMC11396662
  22. [24]H. Leonard, CDKL5 deficiency disorder: Clinical features, diagnosis, and management. Lancet Neurol. 21, 563– 576 (2022). 35483386 PMC9788833
  23. [25]S. Fehr, The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur. J. Hum. Genet. 21, 266– 273 (2013). 22872100 PMC3573195
  24. [26]S. Ricciardi, CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat. Cell Biol. 14, 911– 923 (2012). 22922712 PMC6485419
  25. [27]P. J. Mulcahey, Aged heterozygous Cdkl5 mutant mice exhibit spontaneous epileptic spasms. Exp. Neurol. 332, 113388 (2020). 32585155 PMC8855336
  26. [28]E. Amendola, Mapping pathological phenotypes in a mouse model of CDKL5 disorder. PLoS One 9, e91613 (2014). 24838000 PMC4023934
  27. [29]K. Okuda, Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory. PLoS One 13, e0196587 (2018). 29702698 PMC5922552
  28. [30]J. Wang, Taok1 haploinsufficiency leads to autistic-like behaviors in mice via the dorsal raphe nucleus. Cell Rep. 42, 113078 (2023). 37656623
  29. [31]H. F. Bauer, J. P. Delling, J. Bockmann, T. M. Boeckers, M. Schön, Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders. Front. Behav. Neurosci. 16, 1051175 (2023). 36699652 PMC9868822
  30. [32]M. Schoen, Shank3 transgenic and prenatal zinc-deficient autism mouse models show convergent and individual alterations of brain structures in MRI. Front. Neural Circuits 13, 6 (2019). 30853900 PMC6395436
  31. [33]E. Matas, Major motor and gait deficits with sexual dimorphism in a Shank3 mutant mouse model. Mol. Autism 12, 2 (2021). 33468258 PMC7814442
  32. [34]X. Wang, Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093– 3108 (2011). 21558424 PMC3131048
  33. [35]R. Y. Tsien, Very long-term memories may be stored in the pattern of holes in the perineuronal net. Proc. Natl. Acad. Sci. U.S.A. 110, 12456– 12461 (2013). 23832785 PMC3725115
  34. [36]T. M. Dankovich, S. O. Rizzoli, The synaptic extracellular matrix: Long-lived, stable, and still remarkably dynamic. Front. Synaptic Neurosci. 14, 854956 (2022). 35350469 PMC8957932
  35. [37]E. Bulovaite, A brain atlas of synapse protein lifetime across the mouse lifespan. Neuron 110, 4057– 4073.e8 (2022). 36202095 PMC9789179
  36. [38]B. Mohar, DELTA: A method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning. Nat. Neurosci. 28, 1089– 1098 (2025). 40164741 PMC12081306
  37. [39]S. Heo, T. Kang, A. M. Bygrave, M. R. Larsen, R. L. Huganir, Experience-induced remodeling of the hippocampal post-synaptic proteome and phosphoproteome. Mol. Cell. Proteomics 22, 100661 (2023). 37806341 PMC10652125
  38. [40]Y. Perez-Riverol, The PRIDE database resources in 2022: A hub for mass spectrometry-based proteomics evidences. Nucleic Acids Res. 50, D543– D552 (2022). 34723319 PMC8728295
  39. [41]A. Nightingale, The Proteins API: Accessing key integrated protein and genome information. Nucleic Acids Res. 45, W539– W544 (2017). 28383659 PMC5570157
  40. [43]D. Szklarczyk, The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 51, D638– D646 (2023). 36370105 PMC9825434

Cited by

Sorted by citations

Authors
Heo, S., Zhang, S., Mun, D.-G., Pandey, A., Bygrave, A. M., & Huganir, R. L.
Affiliations
  • Johns Hopkins University (US)
  • Tufts University (US)
  • Mayo Clinic (US)
Corresponding author
  • Heo, Seok
  • Zhang, Shiyu
  • Mun, Dong-Gi
  • Bygrave, Alexei M.
  • Huganir, Richard L.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2026-07-07
Volume
123
Issue
28
Pages
e2602111123-e2602111123
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2602111123
PMC
PMC13367811
OpenAlex
W4416715185
Cited by
5
References
3
Citations by year
2026: 5
FWCI
9.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
HHS | National Institutes of Health (R01MH112152, R37NS036715, R00MH124920, U01CA271410, P30CA15083)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
long-lived proteins, postsynaptic density, sex differences, learning and memory, GABRG2, SHANK3, contextual fear conditioning, hippocampus, synaptic plasticity, protein stability

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