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Cited by 39Neuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology ResearchNeurogenesis and neuroplasticity mechanisms

Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions

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De Felice, E., Gonçalves de Andrade, E., Golia, M. T., González Ibáñez, F., Khakpour, M., Di Castro, M. A., Garofalo, S., Di Pietro, E. +9 more·2022·Journal of Neuroinflammation
DOI 10.1186/s12974-022-02655-zPMC PMC9730634
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Abstract

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia–neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1–CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1 , Tnf-α , Il-6 , and Bdnf , essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K + currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

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  • Images were blinded to experimental groups for density and morphology analyses.

    “The images were blinded to the experimental groups and analysed using Fiji (NIH; v.1.53), as previously reported [56, 64].”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [56]

    The Methods section (Light and electron microscopy; page unavailable) says the images used for density analysis were blindly analyzed. It describes a separate morphology analysis but does not say whether that analysis was blinded to experimental groups. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Few other studies have shown sex-specific differences in microglia between regions and layers of the hippocampus.

    “Few other studies have shown sex-specific differences in microglia between regions and layers of the hippocampus [16, 56–58]”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [56]

    The Introduction reports regional and interlaminar differences in hippocampal microglia in adult male mice. But the Discussion’s “Future perspectives” section says this study examined males and that possible sex differences between hippocampal poles remain to be clarified. It therefore does not establish the claimed sex-specific differences between hippocampal regions or layers. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Ultrastructural analyses were performed using QuPath on images blinded to both animal and group.

    “The microglial ultrastructural analyses was performed using QuPath (v.0.4.4) [71] on images blinded to both animal and group, following an adaptation from our previous work [56, 64].”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [56]

    The Methods section (Light and electron microscopy; page unavailable) says the electron-microscopy analysis used QuPath and was blinded to animal and hippocampal pole. It supports the QuPath method and animal blinding, but specifies hippocampal pole rather than blinding to a general experimental group. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
De Felice, E., Gonçalves de Andrade, E., Golia, M. T., González Ibáñez, F., Khakpour, M., Di Castro, M. A., Garofalo, S., Di Pietro, E., Benatti, C., Brunello, N., Tascedda, F., Kaminska, B., Limatola, C., Ragozzino, D., Tremblay, M. E., Alboni, S., & Maggi, L.
Affiliations
  • Sapienza University of Rome (IT)
  • University of Victoria (CA)
  • University of Modena and Reggio Emilia (IT)
  • Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
  • Istituto Neurologico Mediterraneo (IT)
  • Fondazione Santa Lucia (IT)
Corresponding author
Maggi, L.
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2022-12-08
Volume
19
Issue
1
Pages
292-292
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-022-02655-z
PMC
PMC9730634
OpenAlex
W4311573130
Cited by
39
References
26
Citations by year
2026: 11 · 2025: 13 · 2024: 11 · 2023: 4
FWCI
2.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders
  • Avvio alla Ricerca 2021 (AR22117A67612A07)
  • National Research and Development Center, Poland to B.K (ERA-NET-NEURON/18/2018)
  • Ministero dell'Università e della Ricerca (PRIN 20178L7WRS_001, PRIN 2017HPTFFC_003)
  • Ministero della salute, progetto di ricerca finalizzata (RF-2018-12366215)
  • Associazione Italiana per la Ricerca sul Cancro (AIRC2019 IG-23010)
  • Istituto Pasteur-Fondazione Cenci Bolognetti
  • ERA-NET-NEURON (18/2018)
  • Mexican Council of Science and Technology Grant (CONACYT)
  • Natural Sciences and Research Council of Canada (NSERC) Discovery Grant (RGPIN-2014-05308)
  • FAR grant “Fondo di Ateneo per la Ricerca 2021” (FAR_DIP2021)
  • Fondo di Ateno per la Ricerca 2019 (RM11916B7EE9E512)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
microglia, hippocampus, dorsal hippocampus, ventral hippocampus, long-term potentiation, synaptic plasticity, microglial phenotype, microglial morphology, lysosomes, MERTK, CD68, outward potassium current, interleukin-1, TNF-α, interleukin-6, brain-derived neurotrophic factor, minocycline, PLX5622, neuron-microglia communication
MeSH terms
Animals, Male, Neuronal Plasticity, Mice

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