CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity
Open accessAbstract
The protective/neurotoxic role of fractalkine (CX3CL1) and its receptor CX3C chemokine receptor 1 (CX3CR1) signaling in neurodegenerative disease is an intricate and highly debated research topic and it is becoming even more complicated as new studies reveal discordant results. It appears that the CX3CL1/CX3CR1 axis plays a direct role in neurodegeneration and/or neuroprotection depending on the CNS insult. However, all the above studies focused on the role of CX3CL1/CX3CR1 signaling in pathological conditions, ignoring the relevance of CX3CL1/CX3CR1 signaling under physiological conditions. No approach to date has been taken to decipher the significance of defects in CX3CL1/CX3CR1 signaling in physiological condition. In the present study we used CX3CR1⁻/⁻, CX3CR1⁺/⁻, and wild-type mice to investigate the physiological role of CX3CR1 receptor in cognition and synaptic plasticity. Our results demonstrate for the first time that mice lacking the CX3CR1 receptor show contextual fear conditioning and Morris water maze deficits. CX3CR1 deficiency also affects motor learning. Importantly, mice lacking the receptor have a significant impairment in long-term potentiation (LTP). Infusion with IL-1β receptor antagonist significantly reversed the deficit in cognitive function and impairment in LTP. Our results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1β.
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Evidence suggests CX3CR1 plays an important role in the regulation of synaptic function, with CX3CR1 deficiency resulting in cognitive and LTP impairments indicative of altered synaptic plasticity.
“evidence suggests it plays an important role in the regulation of synaptic function, with CX3CR1 deficiency resulting in cognitive and LTP impairments indicative of altered synaptic plasticity [42, 43].”
From Heterozygous expression of the Alzheimer’s disease-protective PLCγ2 P522R variant enhances Aβ clearance while preserving synapses (2022) · cites this paper as [42]
Activation of the fractalkine receptor (CX3CR1) in microglial cells increases synaptic strength; deficiency in this receptor results in reduced hippocampal synaptic plasticity.
“The activation of the fractalkine receptor (CX3CR1) in microglial cells, increases synaptic strength. However, deficiency in this receptor results in a reduced hippocampal synaptic plasticity (Rogers et al., 2011; Clark et al., 2015).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Rogers et al., 2011
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“Spatial learning was evaluated using the Morris water maze (MWM) task as previously described [40].”
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Madry, C., & Attwell, D. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.637157 · Cited by 109 · see citing works
<i>Cx3cr1-</i> deficient microglia exhibit a premature aging transcriptome
Gyoneva, S., Hosur, R., Gosselin, D., Zhang, B., Ouyang, Z., Cotleur, A. C., Peterson, M., Allaire, N., Challa, R., Cullen, P., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900453 · Cited by 103 · see citing works
“In addition, lack of Cx3cr1 expression reduces adult neurogenesis in the HC and olfactory bulb, and impairs the integration of newborn neurons (Bachstetter et al, 2011; Rogers et al, 2011; Xiao et al, 2015; Sellner et al, 2016; Reshef et al, 2017).”
Microglial modulation of neuronal activity in the healthy brain
York, E. M., Bernier, L., & MacVicar, B. A. (2018) · Developmental Neurobiology · doi:10.1002/dneu.22571 · Cited by 98 · see citing works
Role of Chemokines in the Development and Progression of Alzheimer’s Disease
Wojcieszak, J., Kuczyńska, K., & Zawilska, J. B. (2022) · Journal of Molecular Neuroscience · doi:10.1007/s12031-022-02047-1 · Cited by 97 · see citing works
Microglia communication: parallels between aging and Alzheimer's disease
Udeochu, J. C., Shea, J. M., & Villeda, S. A. (2016) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12307 · Cited by 87 · see citing works
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Pistono, C., Bister, N., Stanová, I., & Malm, T. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.623771 · Cited by 75 · see citing works
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Neuronal Cx3cr1 Deficiency Protects against Amyloid β-Induced Neurotoxicity
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“The exact function of this interaction is not yet clear, but evidence suggests it plays an important role in the regulation of synaptic function, with CX3CR1 deficiency resulting in cognitive and LTP impairments indicative of altered synaptic plasticity [42, 43].”
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Targeting neuroinflammation: The therapeutic potential of ω-3 PUFAs in substance abuse
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- Authors
- Rogers, J. T., Morganti, J. M., Bachstetter, A. D., Hudson, C. E., Peters, M. M., Grimmig, B. A., Weeber, E. J., Bickford, P. C., & Gemma, C.
- Affiliations
- University of South Florida (US)
- James A. Haley Veterans' Hospital (US)
- University of Kentucky (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-11-09
- Volume
- 31
- Issue
- 45
- Pages
- 16241-16250
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3236509
- OpenAlex
- W2099005297
- Cited by
- 624
- References
- 44
- Citations by year
- 2026: 10 · 2025: 29 · 2024: 52 · 2023: 49 · 2022: 47 · 2021: 64 · 2020: 46 · 2019: 53 · 2018: 37 · 2017: 41 · 2016: 56 · 2015: 43 · 2014: 53 · 2013: 28 · 2012: 14
- FWCI
- 16.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service
- National Institute on Aging (P01AG030128, AG04418, P01AG004418)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- CX3CR1, fractalkine, hippocampus, cognitive function, synaptic plasticity, long-term potentiation, contextual fear conditioning, Morris water maze, motor learning, IL-1β, interleukin-1 receptor antagonist, neuroprotection, neurodegeneration
- MeSH terms
- Analysis of Variance, Animals, Behavior, Animal, Biophysics, Bromodeoxyuridine, Calcium-Binding Proteins, Cerebellum, Cognition Disorders, Conditioning, Psychological, Disease Models, Animal, Electric Stimulation, Enzyme-Linked Immunosorbent Assay, Exploratory Behavior, Fear, Gene Expression Regulation, Hippocampus, Male, Mice, Inbred C57BL, Microfilament Proteins, Motor Activity, Cytokines, Microglia, Long-Term Potentiation, Mice, Knockout, Patch-Clamp Techniques, Maze Learning, Excitatory Postsynaptic Potentials, Receptors, Interleukin-8A, Rotarod Performance Test, Mice, Interleukin 1 Receptor Antagonist Protein, Neurogenesis, In Vitro Techniques
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