Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIβ
Open accessAbstract
The Arc/Arg3.1 gene product is rapidly upregulated by strong synaptic activity and critically contributes to weakening synapses by promoting AMPA-R endocytosis. However, how activity-induced Arc is redistributed and determines the synapses to be weakened remains unclear. Here, we show targeting of Arc to inactive synapses via a high-affinity interaction with CaMKIIβ that is not bound to calmodulin. Synaptic Arc accumulates in inactive synapses that previously experienced strong activation and correlates with removal of surface GluA1 from individual synapses. A lack of CaMKIIβ either in vitro or in vivo resulted in loss of Arc upregulation in the silenced synapses. The discovery of Arc's role in "inverse" synaptic tagging that is specific for weaker synapses and prevents undesired enhancement of weak synapses in potentiated neurons reconciles essential roles of Arc both for the late phase of long-term plasticity and for reduction of surface AMPA-Rs in stimulated neurons.
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βCaMKII serves as an activity sensor: when Ca2+ is low, CaM-free, kinase-deactivated βCaMKII interacts with Arc and facilitates Arc-mediated endocytosis of AMPARs.
“Okuno et al. have shown that βCaMKII serves as an activity sensor; when Ca2+ is low, CaM-free, kinase-deactivated βCaMKII interacts directly with Arc and helps facilitate Arc-mediated endocytosis of AMPARs (Okuno et al., 2012).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Okuno et al., 2012
Food intake activates vagal afferents that reach the nucleus tractus solitarius, where A2 noradrenergic neurons project to the hypothalamus, stimulating hypothalamic oxytocin neurons.
“Food intake activates vagal afferents which reach the nucleus tractus solitarius where A2 noradrenergic neurons (Dahlstroem and Fuxe, 1964) project to the hypothalamus, especially those expressing prolactin-releasing peptide (Okuno et al., 2012), where the hypothalamic oxytocin neurons become stimulated (Okuno et al., 2012).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Okuno et al., 2012
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- Authors
- Okuno, H., Akashi, K., Ishii, Y., Yagishita-Kyo, N., Suzuki, K., Nonaka, M., Kawashima, T., Fujii, H., Takemoto-Kimura, S., Abe, M., Natsume, R., Chowdhury, S., Sakimura, K., Worley, P. F., & Bito, H.
- Affiliations
- Japan Science and Technology Agency (JP)
- Brain Research Institute, Niigata University (JP)
- The University of Tokyo (JP)
- Johns Hopkins University (US)
- Corresponding author
- Okuno, Hiroyuki
- Bito, Haruhiko
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 149
- Issue
- 4
- Pages
- 886-898
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4856149
- OpenAlex
- W2113849086
- Cited by
- 310
- References
- 50
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 20 · 2023: 17 · 2022: 19 · 2021: 21 · 2020: 23 · 2019: 22 · 2018: 29 · 2017: 31 · 2016: 17 · 2015: 21 · 2014: 34 · 2013: 17 · 2012: 8
- FWCI
- 10.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (24700321, 221S0003, 21500301, 20670002, 23680040, 22800011, 24300117)
- National Institute of Mental Health (R01MH053608)
- 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 › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Arc/Arg3.1, CaMKIIβ, synaptic tagging, AMPA receptor endocytosis, GluR1, long-term synaptic plasticity, synaptic depression
- MeSH terms
- Animals, Cells, Cultured, Cytoskeletal Proteins, Hippocampus, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Synapses, Rats, Sprague-Dawley, Dendritic Spines, Mice, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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