Epigenetic regulation of microglial phosphatidylinositol 3‐kinase pathway involved in long‐term potentiation and synaptic plasticity in rats
Open accessAbstract
Microglia are the main form of immune defense in the central nervous system. Microglia express phosphatidylinositol 3‐kinase (PI3K), which has been shown to play a significant role in synaptic plasticity in neurons and inflammation via microglia. This study shows that microglial PI3K is regulated epigenetically through histone modifications and posttranslationally through sumoylation and is involved in long‐term potentiation (LTP) by modulating the expression of brain‐derived neurotrophic factor (BDNF), which has been shown to be involved in neuronal synaptic plasticity. Sodium butyrate, a histone deacetylase inhibitor, upregulates PI3K expression, the phosphorylation of its downstream effectors, AKT and cAMP response element‐binding protein (CREB), and the expression of BDNF in microglia, suggesting that BDNF secretion is regulated in microglia via epigenetic regulation of PI3K. Further, knockdown of SUMO1 in BV2 microglia results in a decrease in the expression of PI3K, the phosphorylation of AKT and CREB, as well as the expression of BDNF. These results suggest that microglial PI3K is epigenetically regulated by histone modifications and posttranslationally modified by sumoylation, leading to altered expression of BDNF. Whole‐cell voltage‐clamp showed the involvement of microglia in neuronal LTP, as selective ablation or disruption of microglia with clodronate in rat hippocampal slices abolished LTP. However, LTP was rescued when the same hippocampal slices were treated with active PI3K or BDNF, indicating that microglial PI3K/AKT signaling contributes to LTP and synaptic plasticity. Understanding the mechanisms by which microglial PI3K influences synapses provides insights into the ways it can modulate synaptic transmission and plasticity in learning and memory.
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Microglia play a crucial role in the modulation of synaptic plasticity.
“Microglia also play a crucial role in the modulation of synaptic plasticity.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [87]
Microglial BDNF contributes to learning-dependent synapse formation.
“Of note, a recent study reported the significant contribution of microglial brain-derived neurotrophic factor (BDNF) towards learning-dependent synapse formation (Parkhurst et al., 2013; Saw et al., 2020).”
From miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A (2020) · cites this paper as Saw et al., 2020
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- Authors
- Saw, G., Krishna, K., Gupta, N., Soong, T. W., Mallilankaraman, K., Sajikumar, S., & Dheen, S. T.
- Affiliations
- National University of Singapore (SG)
- Corresponding author
- Sajikumar, Sreedharan
- Dheen, S. Thameem
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2019-11-08
- Volume
- 68
- Issue
- 3
- Pages
- 656-669
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC7003906
- OpenAlex
- W2984798457
- Cited by
- 87
- References
- 54
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 15 · 2023: 14 · 2022: 9 · 2021: 14 · 2020: 5
- FWCI
- 3.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Glia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- microglia, phosphatidylinositol 3-kinase, epigenetic regulation, histone modifications, SUMOylation, SUMO1, brain-derived neurotrophic factor, long-term potentiation, synaptic plasticity, Akt phosphorylation, CREB, histone deacetylase inhibition, sodium butyrate, clodronate, hippocampus, microglial ablation
- MeSH terms
- Animals, Hippocampus, Memory, Neuronal Plasticity, Neurons, Synapses, Signal Transduction, Microglia, Long-Term Potentiation, Phosphatidylinositol 3-Kinases, Epigenesis, Genetic, Rats
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