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Elimination of Microglia Improves Functional Outcomes Following Extensive Neuronal Loss in the Hippocampus
Open accessAbstract
With severe injury or disease, microglia become chronically activated and damage the local brain environment, likely contributing to cognitive decline. We previously discovered that microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for survival in the healthy adult brain, and we have exploited this dependence to determine whether such activated microglia contribute deleteriously to functional recovery following a neuronal lesion. Here, we induced a hippocampal lesion in mice for 25 d via neuronal expression of diphtheria toxin A-chain, producing both a neuroinflammatory reaction and behavioral alterations. Following the 25 d lesion, we administered PLX3397, a CSF1R inhibitor, for 30 d to eliminate microglia. This post-lesion treatment paradigm improved functional recovery on elevated plus maze and Morris water maze, concomitant with reductions in elevated proinflammatory molecules, as well as normalization of lesion-induced alterations in synaptophysin and PSD-95. Further exploration of the effects of microglia on synapses in a second cohort of mice revealed that dendritic spine densities are increased with long-term microglial elimination, providing evidence that microglia shape the synaptic landscape in the adult mouse brain. Furthermore, in these same animals, we determined that microglia play a protective role during lesioning, whereby neuronal loss was potentiated in the absence of these cells. Collectively, we demonstrate that microglia exert beneficial effects during a diphtheria toxin-induced neuronal lesion, but impede recovery following insult. SIGNIFICANCE STATEMENT: It remains unknown to what degree, and by what mechanisms, chronically activated microglia contribute to cognitive deficits associated with brain insults. We induced a genetic neuronal lesion in mice for 25 d and found activated microglia to increase inflammation, alter synaptic surrogates, and impede behavioral recovery. These lesion-associated deficits were ameliorated with subsequent microglial elimination, underscoring the importance of developing therapeutics aimed at eliminating/modulating chronic microglial activation. Additionally, we found long-term microglial depletion globally increases dendritic spines by ∼35% in the adult brain, indicating that microglia continue to sculpt the synaptic landscape in the postdevelopmental brain under homeostatic conditions. Microglial manipulation can therefore be used to investigate the utility of increasing dendritic spine numbers in postnatal conditions displaying synaptic aberrations.
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“In mouse models of AD genetic or pharmacological depletion of microglia prevented microglia association with amyloid plaques and neuronal loss, which led to improved learning and memory without affecting amyloid plaque load in mouse brain (Dagher et al., 2015; Rice et al., 2015; Spangenberg et al., 2016).”
From Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response (2021) · cites this paper as Rice et al., 2015
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“Similarly, CSF1R inhibition after a chronic hippocampal lesion model of brain injury improved behavioral recovery, reduced pro-inflammatory molecules, and increased dendritic spines (239).”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [239]
Experimental — accuracy not yet measuredIn the citing paper
“evidence indicates that these cells interact with and modulate neuronal and synaptic elements, with direct effects on learning and memory [14], [15], [16], [17], [18], [19].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [16]
In the citing paper
“Microglial depletion also enhances performance in certain memory tasks [12, 14, 16] and prevents the forgetting of remote memories, and in association, the dissociation of memory engram cells in healthy adult mice [18].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [16]
In the citing paper
“indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [18]
In the citing paper
“In the MWM probe trial, PLX5622-treated wild-type mice tended to spend more time in the platform zone compared to wild-type mice (Fig. 3k), indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [18]
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“Our studies also revealed that microglial elimination following neuronal insult improved functional outcomes, whereas elimination of microglia during the lesion exacerbated neuronal loss, revealing differential roles of microglia in injury response (Rice et al., 2015).”
ResultSelf-citationMicroglia mediate forgetting via complement-dependent synaptic elimination
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Self-citation
Metadata
- Authors
- Rice, R. A., Spangenberg, E. E., Yamate-Morgan, H., Lee, R. J., Arora, R. P. S., Hernandez, M. X., Tenner, A. J., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Plexxikon (United States) (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-07-08
- Volume
- 35
- Issue
- 27
- Pages
- 9977-9989
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4495246
- OpenAlex
- W1920357305
- Cited by
- 270
- References
- 41
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 27 · 2023: 40 · 2022: 19 · 2021: 43 · 2020: 35 · 2019: 26 · 2018: 20 · 2017: 15 · 2016: 19 · 2015: 2
- FWCI
- 9.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association
- Whitehall Foundation
- Plexxikon
- National Institutes of Health (UL1TR001414, AG016573, AG00538, AG000096)
- National Institute on Aging (P01AG000538, AG-016573, AG 00538, AG000096, PPG AG 00538, P50AG016573, T32AG000096)
- National Institute of Neurological Disorders and Stroke (F31NS086409, R01NS083801)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, CSF1R inhibition, PLX3397, hippocampal lesions, neuronal loss, neuroinflammation, cognitive recovery, dendritic spines, synaptic plasticity, PSD-95, synaptophysin, diphtheria toxin A chain
- MeSH terms
- Aminopyridines, Animals, Behavioral Symptoms, Blood-Brain Barrier, Brain Injuries, Cognition Disorders, Disease Models, Animal, Doxycycline, Female, Hippocampus, Male, Mice, Transgenic, Neurons, Phosphopyruvate Hydratase, Pyrroles, Synaptophysin, Microglia, Maze Learning, Recovery of Function, Dendritic Spines, Mice
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