Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling
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Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate synaptic plasticity. TrkB triggers three downstream signaling pathways; Phosphatidylinositol 3-kinase (PI3K), Phospholipase Cγ (PLCγ) and Mitogen activated protein kinases/Extracellular signal-regulated kinases (MAPK/ERK). We previously showed two distinct mechanisms whereby BDNF-TrkB pathway controls trafficking of PSD-95, which is the major scaffold at excitatory synapses and is critical for synapse maturation. BDNF activates the PI3K-Akt pathway and regulates synaptic delivery of PSD-95 via vesicular transport (Yoshii and Constantine-Paton, 2007). BDNF-TrkB signaling also triggers PSD-95 palmitoylation and its transport to synapses through the phosphorylation of the palmitoylation enzyme ZDHHC8 by a protein kinase C (PKC; Yoshii etal., 2011). The second study used PKC inhibitors chelerythrine as well as a synthetic zeta inhibitory peptide (ZIP) which was originally designed to block the brain-specific PKC isoform protein kinase Mϖ (PKMϖ). However, recent studies raise concerns about specificity of ZIP. Here, we assessed the contribution of TrkB and its three downstream pathways to the synaptic distribution of endogenous PSD-95 in cultured neurons using chemical and genetic interventions. We confirmed that TrkB, PLC, and PI3K were critical for the postsynaptic distribution of PSD-95. Furthermore, suppression of MAPK/ERK also disrupted PSD-95 expression. Next, we examined the contribution of PKC. While both chelerythrine and ZIP suppressed the postsynaptic localization of PSD-95, RNA interference for PKMϖ did not have a significant effect. This result suggests that the ZIP peptide, widely used as the "specific" PKMϖ antagonist by many investigators may block a PKC variant other than PKMϖ such as PKCλ/ι. Our results indicate that TrkB regulates postsynaptic localization of PSD-95 through all three downstream pathways, but also recommend further work to identify other PKC variants that regulate palmitoylation and synaptic localization of PSD-95.
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BDNF-TrkB signaling pathways regulate dendritic growth, synapse development, learning- and memory-processes-dependent synaptic plasticity, apoptosis, and survival of neurons.
“BDNF-TrkB signaling pathways regulate multiple events, such as dendritic growth, pine maturation and stabilization [41,42,43], development of synapses [44,45], learning- and memory-processes-dependent synaptic plasticity [40,46,47], apoptosis, and survival of neurons [48,49,50,51].”
From BDNF as a Promising Therapeutic Agent in Parkinson’s Disease (2020) · cites this paper as [44]
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- Xu B. Zang K. Ruff N. L. Zhang Y. A. Mcconnell S. K. Stryker M. P. (2000). Cortical degeneration in the absence of neurotrophin signaling: dendritic retraction and neuronal loss after removal of the receptor TrkB. Neuron 26 233– 245 10.1016/S0896-6273(00)81153-8 10798407 · DOI
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- Authors
- Yoshii, A., & Constantine-Paton, M.
- Affiliations
- McGovern Institute for Brain Research (US)
- Corresponding author
- Yoshii, Akira
- ORCID
- Yoshii, Akira
- Venue
- Frontiers in Synaptic Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2014-03-31
- Volume
- 6
- Pages
- 6-6
- ISSN
- 1663-3563 (ISSN-L)
- PMC
- PMC3978359
- OpenAlex
- W2049929625
- Cited by
- 93
- References
- 50
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 10 · 2023: 8 · 2022: 7 · 2021: 4 · 2020: 12 · 2019: 3 · 2018: 15 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 1 · 2013: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
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- cc-by
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- Frontiers in Synaptic Neuroscience (publishedVersion, cc-by)
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- Frontiers Research Foundation
- Funders
- Johns Hopkins University
- National Institutes of Health (5r01ey014074-15)
- University of California, San Francisco
- National Eye Institute (R01-EY014074, R01EY006039)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- PSD-95, TrkB signaling, brain-derived neurotrophic factor, postsynaptic localization, phosphatidylinositol 3-kinase, phospholipase C-gamma, MAPK/ERK pathway, protein kinase C, PKMzeta, chelerythrine, palmitoylation, synaptic plasticity, excitatory synapses, synapse maturation
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