PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity
Open accessAbstract
Activity-dependent remodelling of dendritic spines is essential for neural circuit development and synaptic plasticity, but the precise molecular mechanisms that regulate this process are unclear. Activators of Arp2/3-mediated actin polymerisation are required for spine enlargement; however, during long-term depression (LTD), spines shrink via actin depolymerisation and Arp2/3 inhibitors in this process have not yet been identified. Here, we show that PICK1 regulates spine size in hippocampal neurons via inhibition of the Arp2/3 complex. PICK1 knockdown increases spine size, whereas PICK1 overexpression reduces spine size. NMDA receptor activation results in spine shrinkage, which is blocked by PICK1 knockdown or overexpression of a PICK1 mutant that cannot bind Arp2/3. Furthermore, we show that PICK1-Arp2/3 interactions are required for functional hippocampal LTD. This work demonstrates that PICK1 is a novel regulator of spine dynamics. Via Arp2/3 inhibition, PICK1 has complementary yet distinct roles during LTD to regulate AMPA receptor trafficking and spine size, and therefore functions as a crucial factor in both structural and functional plasticity.
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Brief bath application of 20 μM NMDA plus 20 μM glycine induces a 15-20% spine shrinkage within 40 min, measured as a decrease in spine volume without a concomitant change in spine diameter or length.
“Brief bath application of 20 μM NMDA plus 20 μM glycine induces a 15–20% spine shrinkage within a timeframe of 40 min, which is measured as a decrease in spine volume without a concomitant change in either spine diameter or length (Figures 4f and g; Supplementary Figures 6E and F).”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [38]
The Results section (page unavailable) reports significant spine shrinkage after 20 μM NMDA plus 20 μM glycine, and the Methods describe a 3-minute application followed by 40 minutes before fixation. But the paper measures cross-sectional area, not volume, and does not report unchanged spine diameter or length under this treatment; its live-imaging result of 19% shrinkage is at 52 minutes, not 40. (LLM, conf=0.88)
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- Authors
- Nakamura, Y., Wood, C. L., Patton, A. P., Jaafari, N., Henley, J. M., Mellor, J. R., & Hanley, J. G.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Hanley, Jonathan G
- Venue
- The EMBO Journal
- Published
- 2011-01-21
- Volume
- 30
- Issue
- 4
- Pages
- 719-730
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC3041953
- OpenAlex
- W1930654099
- Cited by
- 97
- References
- 40
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 4 · 2019: 4 · 2018: 8 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 17 · 2013: 16 · 2012: 8
- FWCI
- 6.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Wellcome Trust (083721)
- Engineering and Physical Sciences Research Council (EP/E500110/1)
- 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
- PICK1, Arp2/3 complex, synaptic plasticity, long-term depression, actin polymerization, actin depolymerization, NMDA receptor, AMPA receptor trafficking, hippocampal neurons, spine dynamics, structural plasticity
- MeSH terms
- Animals, Animals, Newborn, Carrier Proteins, Cells, Cultured, Cytoskeletal Proteins, Embryo, Mammalian, Neuronal Plasticity, Neurons, Nuclear Proteins, Synapses, Receptors, N-Methyl-D-Aspartate, Rats, Wistar, RNA, Small Interfering, Dendritic Spines, Actin-Related Protein 2-3 Complex, Rats, Organelle Size
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