Activity-dependent redistribution of CaMKII in the postsynaptic compartment of hippocampal neurons
Open accessAbstract
Calcium/calmodulin-dependent protein kinase II (CaMKII), an abundant protein in neurons, is involved in synaptic plasticity and learning. CaMKII associates with multiple proteins located at or near the postsynaptic density (PSD), and CaMKII is known to translocate from cytoplasm to PSD under excitatory conditions. The present study examined the laminar distribution of CaMKII at the PSD by immunogold labeling in dissociated hippocampal cultures under low calcium (EGTA or APV), control, and stimulated (depolarization with high K+ or NMDA) conditions. The patterns of CaMKII distribution are classified with particular reference to the two layers of the PSD: (1) the PSD core, a layer within ~ 30–40 nm to the postsynaptic membrane, and (2) the PSD pallium, a deeper layer beyond the PSD core, ~ 100–120 nm from the postsynaptic membrane. Under low calcium conditions, a subpopulation (40%) of synapses stood out with no CaMKII labeling at the PSD, indicating that localization of CaMKII at the PSD is sensitive to calcium levels. Under control conditions, the majority (~ 60–70%) of synapses had label for CaMKII dispersed evenly in the spine, including the PSD and the nearby cytoplasm. Upon stimulation, the majority (60–75%) of synapses had label for CaMKII concentrated at the PSD, delineating the PSD pallium from the cytoplasm. Median distance of label for CaMKII to postsynaptic membrane was higher in low calcium samples (68–77 nm), than in control (59–63 nm) and stimulated samples (49–53 nm). Thus, upon stimulation, not only more CaMKII translocated to the PSD, but they also were closer to the postsynaptic membrane. Additionally, there were two relatively infrequent labeling patterns that may represent intermediate stages of CaMKII distribution between basal and stimulated conditions: (1) one type showed label preferentially localized near the PSD core where CaMKII may be binding to NR2B, an NMDA receptor concentrated at the PSD core, and (2) the second type showed label preferentially in the PSD pallium, where CaMKII may be binding to Shank, a PSD scaffold protein located in the PSD pallium. Both of these distribution patterns may portray the initial stages of CaMKII translocation upon synaptic activation. In addition to binding to PSD proteins, the concentrated CaMKII labeling at the PSD under heightened excitatory conditions could also be formed by self-clustering of CaMKII molecules recruited to the PSD. Most importantly, these accumulated CaMKII molecules do not extend beyond the border of the PSD pallium, and are likely held in the pallium by binding to Shank under these conditions.
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Glutamate treatment of neuronal cultures causes CaMKII clustering at excitatory synapses.
“Glutamate treatment of neuronal cultures causes CaMKII clustering at excitatory synapses (136–140).”
From Synaptic memory and CaMKII (2023) · cites this paper as [139]
The Results and Methods describe treating dissociated hippocampal neuronal cultures with NMDA or high K+, not glutamate. The Discussion reports that stimulation concentrated CaMKII at the postsynaptic density, while describing CaMKII self-clustering as a possibility rather than an established mechanism. Thus the synaptic accumulation is supported, but the specified glutamate treatment and definite clustering are not. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMost of these molecules are in the pallium, just beneath the core of the PSD and not close enough to be bound to GluN2B.
“Most of these molecules are in the pallium, just beneath the core of the PSD and not close enough to be bound to GluN2B (139).”
From Synaptic memory and CaMKII (2023) · cites this paper as [139]
The Results describe CaMKII labeling as concentrated particularly in the PSD pallium under stimulation. The Discussion says CaMKII molecules in the distal pallium are too far from NR2B (GluN2B) in the PSD core to bind it directly. It does not establish that most CaMKII molecules are too far away; it also reports labeling in the core. (LLM, conf=0.86)
Experimental — accuracy not yet measuredShank3 resides in the pallium of the PSD, just below the core.
“Shank3 resides in the pallium of the PSD, just below the core (139, 162).”
From Synaptic memory and CaMKII (2023) · cites this paper as [139]
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Cites
Interaction with the NMDA receptor locks CaMKII in an active conformation
Bayer, K.-U., De Koninck, P., Leonard, A. S., Hell, J. W., & Schulman, H. (2001) · Nature · doi:10.1038/35081080 · Cited by 732 · see citing works
Shen, K., & Meyer, T. (1999) · Science · doi:10.1126/science.284.5411.162 · Cited by 673 · see citing works
Ultrastructure of Synapses in the Mammalian BrainPreprint
Harris, K. M., & Weinberg, R. J. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005587 · Cited by 423 · see citing works
CaMKII: Claiming Center Stage in Postsynaptic Function and Organization
Hell, J. W. (2014) · Neuron · doi:10.1016/j.neuron.2013.12.024 · Cited by 352 · see citing works
Shen, K., Teruel, M. N., Subramanian, K., & Meyer, T. (1998) · Neuron · doi:10.1016/s0896-6273(00)80569-3 · Cited by 350 · see citing works
Laminar Organization of the NMDA Receptor Complex within the Postsynaptic Density
Valtschanoff, J. G., & Weinberg, R. J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-04-01211.2001 · Cited by 301 · see citing works
Okamoto, K., Bosch, M., & Hayashi, Y. (2009) · Physiology · doi:10.1152/physiol.00029.2009 · Cited by 197 · see citing works
Glutamate-induced transient modification of the postsynaptic density
Dosemeci, A., Tao-Cheng, J.-H., Vinade, L., Winters, C. A., Pozzo-Miller, L., & Reese, T. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181336998 · Cited by 184 · see citing works
Self-citationWalikonis, R. S., Oguni, A., Khorosheva, E. M., Jeng, C.-J., Asuncion, F. J., & Kennedy, M. B. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-02-00423.2001 · Cited by 181 · see citing works
Wyszynski, M., Kharazia, V., Shanghvi, R., Rao, A., Beggs, A. H., Craig, A. M., Weinberg, R., & Sheng, M. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-04-01383.1998 · Cited by 168 · see citing works
Analysis of synaptic ultrastructure without fixative using high‐pressure freezing and tomography
Rostaing, P., Réal, É., Siksou, L., Lechaire, J. P., Boudier, T., Boeckers, T. M., Gertler, F. B., Gundelfinger, E. D., Triller, A., & Marty, S. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05234.x · Cited by 152 · see citing works
The Postsynaptic Density: There Is More than Meets the Eye
Dosemeci, A., Weinberg, R. J., Reese, T. S., & Tao-Cheng, J.-H. (2016) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2016.00023 · Cited by 138 · see citing works
Self-citationShonesy, B. C., Jalan‐Sakrikar, N., Cavener, V. S., & Colbran, R. J. (2014) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-420170-5.00003-9 · Cited by 134 · see citing works
A Novel Particulate Form of Ca<sup>2+</sup>/CaMKII-Dependent Protein Kinase II in Neurons
Dosemeci, A., Reese, T. S., Petersen, J., & Tao-Cheng, J.-H. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-09-03076.2000 · Cited by 124 · see citing works
Self-citationStrack, S., Robison, A. J., Bass, M. A., & Colbran, R. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000319200 · Cited by 116 · see citing works
Tao-Cheng, J.-H., Gallant, P. E., Brightman, M., Döṣemeci, A., & Reese, T. S. (2007) · The Journal of Comparative Neurology · doi:10.1002/cne.21276 · Cited by 116 · see citing works
Self-citationLowenthal, M. S., Markey, S. P., & Döṣemeci, A. (2015) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5b00109 · Cited by 85 · see citing works
Tao-Cheng, J.-H., Thein, S., Yang, Y., Reese, T. S., & Gallant, P. E. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.01.066 · Cited by 84 · see citing works
Self-citationHudmon, A., Aronowski, J., Kolb, S. J., & Waxham, M. N. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.15.8800 · Cited by 76 · see citing works
Baucum, A. J., Shonesy, B. C., Rose, K. L., & Colbran, R. J. (2015) · ACS Chemical Neuroscience · doi:10.1021/cn500337u · Cited by 71 · see citing works
Activity induced changes in the distribution of Shanks at hippocampal synapses
Tao-Cheng, J. H., Dosemeci, A., Gallant, P. E., Smith, C., & Reese, T. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.03.041 · Cited by 61 · see citing works
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Tao-Cheng, J.-H., Toy, D., Winters, C. A., Reese, T. S., & Döṣemeci, A. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153979 · Cited by 59 · see citing works
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Perfitt, T. L., Wang, X., Dickerson, M. T., Stephenson, J. R., Nakagawa, T., Jacobson, D. A., & Colbran, R. J. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0893-19.2020 · Cited by 54 · see citing works
Differential Distribution of Shank and GKAP at the Postsynaptic Density
Tao-Cheng, J.-H., Yang, Y., Reese, T. S., & Döṣemeci, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0118750 · Cited by 46 · see citing works
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Ding, J., Kennedy, M. B., & Weinberg, R. J. (2013) · Journal of Comparative Neurology · doi:10.1002/cne.23372 · Cited by 45 · see citing works
Inhibition of phosphatase activity prolongs NMDA-induced modification of the postsynaptic density
Döṣemeci, A., Vinadé, L., Winters, C. A., Reese, T. S., & Tao-Cheng, J.-H. (2002) · Journal of Neurocytology · doi:10.1023/a:1025735410738 · Cited by 44 · see citing works
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Thein, S. H., Tao-Cheng, J.-H., Li, Y., Bayer, K. U., Reese, T. S., & Döṣemeci, A. (2014) · PLoS ONE · doi:10.1371/journal.pone.0091312 · Cited by 37 · see citing works
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Döṣemeci, A., Burch, A. M., Loo, H., Toy, D., & Tao-Cheng, J.-H. (2017) · PLoS ONE · doi:10.1371/journal.pone.0190250 · Cited by 37 · see citing works
Self-citationTao-Cheng, J.-H. (2019) · Molecular Brain · doi:10.1186/s13041-019-0468-x · Cited by 30 · see citing works
Self-citationTao-Cheng, J.-H., Yang, Y., Bayer, K. U., Reese, T. S., & Döṣemeci, A. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.03.063 · Cited by 28 · see citing works
Self-citationDistribution of densin in neurons
Döṣemeci, A., Tao-Cheng, J.-H., Loo, H., & Reese, T. S. (2018) · PLoS ONE · doi:10.1371/journal.pone.0205859 · Cited by 15 · see citing works
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CaMKII: a central molecular organizer of synaptic plasticity, learning and memory
Yasuda, R., Hayashi, Y., & Hell, J. W. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-022-00624-2 · Cited by 431 · see citing works
Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works
“Shank3 resides in the pallium of the PSD, just below the core (139, 162).”
BackgroundCaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation
Cai, Q., Zeng, M., Wu, X., Wu, H., Zhan, Y., Tian, R., & Zhang, M. (2021) · Cell Research · doi:10.1038/s41422-020-00439-9 · Cited by 83 · see citing works
Liang, F., Li, M., Xu, M., Zhang, Y., Dong, Y., Soriano, S. G., McCann, M. E., Yang, G., & Xie, Z. (2023) · British Journal of Anaesthesia · doi:10.1016/j.bja.2023.06.059 · Cited by 35 · see citing works
Tao-Cheng, J.-H., Crocker, V. T., Moreira, S. L., & Azzam, R. N. (2021) · Molecular Brain · doi:10.1186/s13041-021-00799-2 · Cited by 30 · see citing works
Self-citationWu, H., Chen, X., Shen, Z., Li, H., Liang, S., Lu, Y., & Zhang, M. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.11.011 · Cited by 30 · see citing works
A new perspective on hippocampal synaptic plasticity and post‐stroke depression
Sun, N., Cui, W., Min, X., Zhang, G., Liu, J., & Wu, H. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.16093 · Cited by 23 · see citing works
CaMKII Phosphorylation Regulates Synaptic Enrichment of Shank3
Jeong, J., Li, Y., & Roche, K. W. (2021) · eNeuro · doi:10.1523/eneuro.0481-20.2021 · Cited by 20 · see citing works
Synaptic PSD-95 biology: from localization and interactors to N-terminus function
Alkaas, A., Kurup, P., Kanuru, S., Rommel, A. V., Singh, T., Patel, M. J., & Delgado, J. Y. (2025) · Journal of Neurophysiology · doi:10.1152/jn.00272.2025 · Cited by 16 · see citing works
Feng, Z., Wu, X., & Zhang, M. (2021) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108622 · Cited by 16 · see citing works
Phase Separation–Mediated Compartmentalization Underlies Synapse Formation and Plasticity
Wu, X., Shen, Z., & Zhang, M. (2025) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-112723-040159 · Cited by 14 · see citing works
The lateral habenula integrates age and experience to promote social transitions in developing rats
Cobb-Lewis, D. E., George, A., Hu, S., Packard, K., Song, M., Nikitah, I., Nguyen-Lopez, O., Tesone, E., Rowden, J., Wang, J., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114556 · Cited by 11 · see citing works
Sadiq, A., Funk, A. T., & Waugh, J. L. (2025) · Frontiers in Neural Circuits · doi:10.3389/fncir.2025.1514937 · Cited by 11 · see citing works
Interactions with PDZ proteins diversify voltage‐gated calcium channel signaling
Wang, S., & Cortés, C. J. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24650 · Cited by 9 · see citing works
Soma-localized Rab39 inhibits synaptic autophagy by controlling trafficking of Atg9 vesicles
Kilic, A., Özturan, G., Vandekerkhove, D., Kuenen, S., Swerts, J., Pedrazo, E. M., Calatayud, C., Escamilla‐Ayala, A., Corthout, N., Hernández-Varas, P., et al. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00536-8 · Cited by 8 · see citing works
Inhibitory postsynaptic density from the lens of phase separation
Bai, G., & Zhang, M. (2022) · Oxford Open Neuroscience · doi:10.1093/oons/kvac003 · Cited by 7 · see citing works
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Tao-Cheng, J.-H., Moreira, S. L., Winters, C. A., Reese, T. S., & Döṣemeci, A. (2023) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2023.1239098 · Cited by 7 · see citing works
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Zhu, S., Shen, Z., Wu, X., & Zhang, M. (2025) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2025.102975 · Cited by 7 · see citing works
Shaikh, J., Nagarajan, A., Mitra, T., Modak, A. S., Biswas, K., Meher, G., Bhausaheb, A. J., Kannan, N. A., Sahu, B. S., Ghatak, S., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70840-2 · Cited by 5 · see citing works
Yamazaki, H., Koganezawa, N., Yokoo, H., Sekino, Y., & Shirao, T. (2023) · Neuroscience Research · doi:10.1016/j.neures.2023.08.002 · Cited by 5 · see citing works
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Caterino, C., Ugolini, M., Durso, W., Jevdokimenko, K., Groth, M., Riege, K., Görlach, M., Fornasiero, E. F., Ori, A., Hoffman, S., et al. (2025) · Aging Cell · doi:10.1111/acel.70262 · Cited by 5 · see citing works
Dai, W., Zhao, M., Chen, C., Zhou, C., Wang, P., Yang, Z., Gao, S., Lu, Y., Zhang, J., & Liu, X. (2022) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.2c00569 · Cited by 4 · see citing works
Podestà, A., Monni, L., Arnold, F., Arnold, J., Bertelli, S., Xu, R., Onken, J., Thomale, U., Kalbhenn, T., Simon, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.14.653650 · Cited by 3 · see citing works
Canney, M. S., Bouchoux, G., Carpentier, A. C., & Rossi, P. D. (2025) · Ultrasound in Medicine & Biology · doi:10.1016/j.ultrasmedbio.2025.10.008 · Cited by 2 · see citing works
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Rigter, P. M. F., Bezstarosti, K., Koc, O. C., Perfitt, T. L., Demmers, J., Colbran, R. J., Stratton, M. M., Elgersma, Y., & van Woerden, G. M. (2026) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00779 · Cited by 1 · see citing works
Tao-Cheng, J.-H., Crocker, V. T., Moreira, S. L., & Azzam, R. N. (2021) · Research Square · doi:10.21203/rs.3.rs-268115/v1
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- Authors
- Tao-Cheng, J.-H.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Tao-Cheng, Jung-Hwa
- ORCID
- Tao-Cheng, Jung-Hwa
- Venue
- Molecular Brain
- Published
- 2020-04-01
- Volume
- 13
- Issue
- 1
- Pages
- 53-53
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC7110642
- OpenAlex
- W3014800409
- Cited by
- 38
- References
- 34
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 3 · 2023: 6 · 2022: 3 · 2021: 13 · 2020: 2
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Neurological Disorders and Stroke (intramural funds)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CaMKII, postsynaptic density, hippocampal neurons, synaptic plasticity, calcium translocation, NMDA receptor, NR2B, shank, synaptic scaffolds, low calcium, synaptic stimulation, dendritic spine morphology, immunogold labeling, synaptic protein localization, learning and memory, synaptic vesicle recycling
- MeSH terms
- Animals, Hippocampus, Neurons, N-Methylaspartate, Rats, Sprague-Dawley, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Post-Synaptic Density
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