Phosphatidylinositol 3-Kinase Regulates the Induction of Long-Term Potentiation through Extracellular Signal-Related Kinase-Independent Mechanisms
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Inhibitors of both phosphatidylinositol-3-kinase (PI3-kinase) and MAPK/ERK (mitogen-activate protein kinase/extracellular signal-related kinase) activation inhibit NMDA receptor-dependent long-term potentiation (LTP). PI3-kinase inhibitors also block activation of ERK by NMDA receptor stimulation, suggesting that PI3-kinase inhibitors block LTP because PI3-kinase is an essential upstream regulator of ERK activation. To examine this hypothesis, we investigated the effects of PI3-kinase inhibitors on ERK activation and LTP induction in the CA1 region of mouse hippocampal slices. Consistent with the notion that ERK activation by NMDA receptor stimulation is PI3-kinase dependent, the PI3-kinase inhibitor wortmannin partially inhibited ERK2 activation induced by bath application of NMDA and strongly suppressed ERK2 activation by high-frequency synaptic stimulation. PI3-kinase and MEK (MAP kinase kinase) inhibitors had very different effects on LTP, however. Both types of inhibitors suppressed LTP induced by theta-frequency trains of synaptic stimulation, but only PI3-kinase inhibitors suppressed the induction of LTP by high-frequency stimulation or low-frequency stimulation paired with postsynaptic depolarization. Concentrations of PI3-kinase inhibitors that inhibited LTP when present during high-frequency stimulation had no effect on potentiated synapses when applied after high-frequency stimulation, suggesting that PI3-kinase is specifically involved in the induction of LTP. Finally, we found that LTP induced by theta-frequency stimulation was MEK inhibitor insensitive but still PI3-kinase dependent in hippocampal slices from PSD-95 (postsynaptic density-95) mutant mice. Together, our results indicate that the role of PI3-kinase in LTP is not limited to its role as an upstream regulator of MAPK signaling but also includes signaling through ERK-independent pathways that regulate LTP induction.
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mBDNF-TrkB-signaling pathways regulate multiple events, such as apoptosis and survival of neurons, dendritic growth, spine maturation and stabilization, development of synapses, and learning- and memory-processes-dependent synaptic plasticity.
“mBDNF-TrkB-signaling pathways regulate multiple events, such as apoptosis and survival of neurons [90,91,92], dendritic growth [93,94,95,96], spine maturation and stabilization, development of synapses [96,97,98], learning- and memory-processes-dependent synaptic plasticity [99,100].”
From Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer (2020) · cites this paper as [99]
The Introduction discusses Ras, PI3-kinase and MAPK signaling in long-term potentiation, but does not connect those findings to mBDNF–TrkB signaling. Searches of our copy for BDNF and TrkB found no passage addressing whether that pathway regulates learning- or memory-related synaptic plasticity. (LLM, conf=0.76)
Experimental — accuracy not yet measuredBDNF-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 [46]
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- Authors
- Opazo, P., Watabe, A. M., Grant, S. G. N., & O'Dell, T. J.
- Affiliations
- University of California, Los Angeles (US)
- University of Edinburgh (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-05-01
- Volume
- 23
- Issue
- 9
- Pages
- 3679-3688
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6742185
- OpenAlex
- W2114842668
- Cited by
- 215
- References
- 4
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 2 · 2017: 7 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 20 · 2012: 11
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- National Institute of Mental Health
- 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
- phosphatidylinositol 3-kinase, long-term potentiation, NMDA receptor, ERK2 activation, MEK inhibition, wortmannin, paired-pulse stimulation, PSD-95, hippocampal CA1, synaptic plasticity
- MeSH terms
- Disks Large Homolog 4 Protein, Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Butadienes, Chromones, Electric Stimulation, Enzyme Inhibitors, Hippocampus, Membrane Proteins, Mice, Inbred C57BL, Morpholines, Nerve Tissue Proteins, Nitriles, Signal Transduction, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Long-Term Potentiation, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Intracellular Signaling Peptides and Proteins, Mice, Guanylate Kinases, In Vitro Techniques
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