A Proinflammatory Stimulus Disrupts Hippocampal Plasticity and Learning via Microglial Activation and 25-Hydroxycholesterol
Open accessAbstract
Inflammatory cells, including macrophages and microglia, synthesize and release the oxysterol 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases the expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild-type microglia produced higher levels of 25HC than Ch25h knock-out (KO) microglia with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo , LPS treatment also disrupts LTP and inhibits one-trial learning in wild-type mice, but not Ch25h KO mice. These results demonstrate that the oxysterol 25HC is a key modulator of synaptic plasticity and memory under proinflammatory stimuli. SIGNIFICANCE STATEMENT Neuroinflammation is thought to contribute to cognitive impairment in multiple neuropsychiatric illnesses. In this study, we found that a proinflammatory stimulus, LPS, disrupts hippocampal LTP via a metaplastic mechanism. The effects of LPS on LTP are mimicked by the oxysterol 25-hydroxycholesterol (25HC), an immune mediator synthesized in brain microglia. Effects of LPS on both synaptic plasticity and one-trial inhibitory avoidance learning are eliminated in mice deficient in Ch25h (cholesterol 25-hydroxylase), the primary enzyme responsible for endogenous 25HC synthesis. Thus, these results indicate that 25HC is a key mediator of the effects of an inflammatory stimulus on hippocampal function and open new potential avenues to overcome the effects of neuroinflammation on brain function.
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25HC disrupts hippocampal plasticity and learning in mice.
“More recently, we showed that 25HC disrupts hippocampal plasticity and learning in mice (16) suggesting that 25HC may also exhibit neuron-specific activities.”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [16]
The Results report that 25HC inhibited hippocampal LTP in mouse slices. They also report that LPS impaired learning in wild-type mice but not in Ch25h knockout mice; the Introduction says this suggests 25HC contributes to impaired learning. The paper does not directly show that administering 25HC disrupts learning in mice, so the claim states that part more definitively than the evidence supports (page numbers unavailable). (LLM, conf=0.88)
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Inflammatory caspases are innate immune receptors for intracellular LPS
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Microglia: Dynamic Mediators of Synapse Development and Plasticity
Wu, Y., Dissing-Olesen, L., MacVicar, B. A., & Stevens, B. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.008 · Cited by 661 · see citing works
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Cholesterol 24-Hydroxylase: an enzyme of cholesterol turnover in the brain
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Neural ageing and synaptic plasticity: prioritizing brain health in healthy longevity
Navakkode, S., & Kennedy, B. K. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1428244 · Cited by 75 · see citing works
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Self-citation
- Authors
- Izumi, Y., Cashikar, A. G., Krishnan, K., Paul, S. M., Covey, D. F., Mennerick, S. J., & Zorumski, C. F.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2021-11-01
- Volume
- 41
- Issue
- 49
- Pages
- 10054-10064
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC8660051
- OpenAlex
- W3211181013
- Cited by
- 53
- References
- 8
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 11 · 2023: 17 · 2022: 6
- FWCI
- 3.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (MH101874, MH114866, MH123748)
- The Taylor Family Institute for Innovative Psychiatric Research
- The Bantly Foundation
- 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
- 25-hydroxycholesterol, oxysterols, microglial activation, lipopolysaccharide, neuroinflammation, hippocampal synaptic plasticity, long-term potentiation, metaplasticity, NMDA receptor, cholesterol 25-hydroxylase, passive avoidance learning, memory impairment
- MeSH terms
- Neuroinflammatory Diseases, Animals, Avoidance Learning, Hippocampus, Hydroxycholesterols, Lipopolysaccharides, Mice, Inbred C57BL, Rats, Sprague-Dawley, Microglia, Long-Term Potentiation, Mice, Knockout, Mice, Rats
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