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Cited by 110Neuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanismsNeurological Disease Mechanisms and Treatments

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Microglia regulate hippocampal neurogenesis during chronic neurodegeneration

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De Lucia, Chiara, Rinchon, Adeline, Olmos-Alonso, Adrian, Riecken, Kristoffer, Fehse, Boris, Boche, Delphine, Perry, V. Hugh, Gomez-Nicola, Diego·2016·Brain, Behavior, and Immunity
DOI 10.1016/j.bbi.2015.11.001PMC PMC4907582
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Abstract

Neurogenesis is altered in neurodegenerative disorders, partly regulated by inflammatory factors. We have investigated whether microglia, the innate immune brain cells, regulate hippocampal neurogenesis in neurodegeneration. Using the ME7 model of prion disease we applied gain- or loss-of CSF1R function, as means to stimulate or inhibit microglial proliferation, respectively, to dissect the contribution of these cells to neurogenesis. We found that increased hippocampal neurogenesis correlates with the expansion of the microglia population. The selective inhibition of microglial proliferation caused a reduction in neurogenesis and a restoration of normal neuronal differentiation, supporting a pro-neurogenic role for microglia. Using a gene screening strategy, we identified TGFβ as a molecule controlling the microglial pro-neurogenic response in chronic neurodegeneration, supported by loss-of-function mechanistic experiments. By the selective targeting of microglial proliferation we have been able to uncover a pro-neurogenic role for microglia in chronic neurodegeneration, suggesting promising therapeutic targets to normalise the neurogenic niche during neurodegeneration.

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Figures

Fig. 1 Increased microglisis in the dentate gyrus of prion-diseased mice. (A–C) Quantification of the density (B) or relative sub-regional distribution (C) of microglial cells (Iba1+) in the dentate gyrus (DG) of prion-diseased mice (ME7; black bars) or NBH controls (normal brain homogenate, open bars). Representative images from c-fms EGFP NBH and ME7 mice shown in A (nuclei shown in red, DAPI). (B) Quantified data expressed as mean ± SEM of the number of Iba1+ cells/mm2. (C) Quantified data expressed as mean ± SEM of the % of Iba1+ cells at a specific layer from the total population of Iba1+ at the dentate gyrus (DG). (D, E) Analysis of the cell-contact interaction of microglial cells (Iba1+) with neural progenitor cells (NPCs, DCX+) at the DG of ME7 or NBH mice. Microglial density was measured at high- or low-density DCX+ clusters. (E) Quantified data expressed as mean ± SEM of the number of Iba1+ cells/mm2 at high/low density DCX+ clusters. Statistical differences: *p < 0.05 (vs. matching NBH area), ***p < 0.001 (vs. matching NBH area). Data were analysed with a two-way ANOVA, showing statistical comparisons arising from a post-hoc Tukey test (n = 4–6). Scale bar in (A, D) 100 μm.
Fig. 1 Increased microglisis in the dentate gyrus of prion-diseased mice. (A–C) Quantification of the density (B) or relative sub-regional distribution (C) of microglial cells (Iba1+) in the dentate gyrus (DG) of prion-diseased mice (ME7; black bars) or NBH controls (normal brain homogenate, open bars). Representative images from c-fms EGFP NBH and ME7 mice shown in A (nuclei shown in red, DAPI). (B) Quantified data expressed as mean ± SEM of the number of Iba1+ cells/mm2. (C) Quantified data expressed as mean ± SEM of the % of Iba1+ cells at a specific layer from the total population of Iba1+ at the dentate gyrus (DG). (D, E) Analysis of the cell-contact interaction of microglial cells (Iba1+) with neural progenitor cells (NPCs, DCX+) at the DG of ME7 or NBH mice. Microglial density was measured at high- or low-density DCX+ clusters. (E) Quantified data expressed as mean ± SEM of the number of Iba1+ cells/mm2 at high/low density DCX+ clusters. Statistical differences: *p < 0.05 (vs. matching NBH area), ***p < 0.001 (vs. matching NBH area). Data were analysed with a two-way ANOVA, showing statistical comparisons arising from a post-hoc Tukey test (n = 4–6). Scale bar in (A, D) 100 μm.CC BY · PubMed Central
Fig. 2 CSF1R is not expressed by neurons, astrocytes or NPCs. (A) Immunohistochemical analysis, coupled to confocal microscopy, of the localisation of EGFP (driven by the c-fms (CSF1R) promoter in macgreen mice) in astrocytes (GFAP+, blue) or neurons (NeuN+, red) in the hippocampus of ME7 mice. (B) Immunohistochemical analysis, coupled to confocal microscopy, of the localisation of EGFP (driven by the c-fms (CSF1R) promoter in macgreen mice) in neural progenitor cells (NPCs, DCX+; red) at the dentate gyrus (DG) of ME7 mice. Nuclei are stained in blue. Scale bar in (A, B) 50 μm.
Fig. 2 CSF1R is not expressed by neurons, astrocytes or NPCs. (A) Immunohistochemical analysis, coupled to confocal microscopy, of the localisation of EGFP (driven by the c-fms (CSF1R) promoter in macgreen mice) in astrocytes (GFAP+, blue) or neurons (NeuN+, red) in the hippocampus of ME7 mice. (B) Immunohistochemical analysis, coupled to confocal microscopy, of the localisation of EGFP (driven by the c-fms (CSF1R) promoter in macgreen mice) in neural progenitor cells (NPCs, DCX+; red) at the dentate gyrus (DG) of ME7 mice. Nuclei are stained in blue. Scale bar in (A, B) 50 μm.CC BY · PubMed Central
Fig. 3 The gain- or loss-of-activity of CSF1R reveals a pro-neurogenic role of microglia in prion disease. (A) Gain of activity of CSF1R was achieved by the intrahippocampal administration of recombinant CSF1, IL34 or vehicle in ME7 mice, while loss of activity of CSF1R achieved by the prolonged oral dosing of GW2580, as previously described (Gomez-Nicola et al., 2013). (B) Analysis of the density of neural progenitor cells (NPCs; DCX+) at the subgranular layer (SGL) of the dentate gyrus (DG) after gain of activity of CSF1R in prion-diseased mice (+CSF1 or +IL34). Quantified data expressed as mean ± SEM of the number of DCX+ cells/mm2. (C–E) Analysis of the density of proliferating cells (BrdU+; D) and NPCs (DCX+; E) at the SGL of the DG after loss of activity of CSF1R in prion-diseased mice (+GW2580). Quantified data expressed as mean ± SEM of the number of BrdU+ or DCX+ cells/mm2. Representative images shown in C. (F–H) Fluorescent marking of neuron generation in the DG by the intraparenchymal (hilus) administration of ecotropic SFFV γ-retroviral (Eco-SFFV-RV) vectors driving the expression of mCherry, in ME7 or NBH mice, treated with GW2580 or control (see A). (F) Projection of confocal Z-stacks of mCherry+ 4-weeks old granule neurons from NBH (normal brain homogenate) or ME7 mice (see A). The maturation of the dendritic trees was analysed according to the Sholl method (G), representing the mean ± SEM of the number of intersections at increasing distances from the cell soma. (H) Quantification of the maximum distance from cell soma (μm) or the total number of dendrites/neuron, in cells traced as described previously, expressed as mean ± SEM. For G, statistical differences: *p < 0.05 ME7 control vs. NBH control, #p < 0.05 ME7 control vs. ME7+GW2580. Data were analysed with a T-test. For B, statistical differences: *p < 0.05 (vs. ME7+Sal). For D, E, H, statistical differences for connected bars: *p < 0.05, **p < 0.01. Data were analysed with a one-way (B) or two-way (D, E, H) ANOVA showing statistical comparisons arising from a post-hoc Tukey test (n = 4–6). Scale bar in (C) 100 μm, (F) 50 μm.
Fig. 3 The gain- or loss-of-activity of CSF1R reveals a pro-neurogenic role of microglia in prion disease. (A) Gain of activity of CSF1R was achieved by the intrahippocampal administration of recombinant CSF1, IL34 or vehicle in ME7 mice, while loss of activity of CSF1R achieved by the prolonged oral dosing of GW2580, as previously described (Gomez-Nicola et al., 2013). (B) Analysis of the density of neural progenitor cells (NPCs; DCX+) at the subgranular layer (SGL) of the dentate gyrus (DG) after gain of activity of CSF1R in prion-diseased mice (+CSF1 or +IL34). Quantified data expressed as mean ± SEM of the number of DCX+ cells/mm2. (C–E) Analysis of the density of proliferating cells (BrdU+; D) and NPCs (DCX+; E) at the SGL of the DG after loss of activity of CSF1R in prion-diseased mice (+GW2580). Quantified data expressed as mean ± SEM of the number of BrdU+ or DCX+ cells/mm2. Representative images shown in C. (F–H) Fluorescent marking of neuron generation in the DG by the intraparenchymal (hilus) administration of ecotropic SFFV γ-retroviral (Eco-SFFV-RV) vectors driving the expression of mCherry, in ME7 or NBH mice, treated with GW2580 or control (see A). (F) Projection of confocal Z-stacks of mCherry+ 4-weeks old granule neurons from NBH (normal brain homogenate) or ME7 mice (see A). The maturation of the dendritic trees was analysed according to the Sholl method (G), representing the mean ± SEM of the number of intersections at increasing distances from the cell soma. (H) Quantification of the maximum distance from cell soma (μm) or the total number of dendrites/neuron, in cells traced as described previously, expressed as mean ± SEM. For G, statistical differences: *p < 0.05 ME7 control vs. NBH control, #p < 0.05 ME7 control vs. ME7+GW2580. Data were analysed with a T-test. For B, statistical differences: *p < 0.05 (vs. ME7+Sal). For D, E, H, statistical differences for connected bars: *p < 0.05, **p < 0.01. Data were analysed with a one-way (B) or two-way (D, E, H) ANOVA showing statistical comparisons arising from a post-hoc Tukey test (n = 4–6). Scale bar in (C) 100 μm, (F) 50 μm.CC BY · PubMed Central
Fig. 4 GW2580 inhibits the proliferation of microglial cells in ME7 mice. Analysis of the impact of the long-term treatment (4 weeks) of NBH (normal brain homogenate) or ME7 mice with control or GW2580, on the number of microglial cells. Representative pictures from the DG, with microglial cells identified by the expression of EGFP (macgreen mice; green). Scale bar 200 μm. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4 GW2580 inhibits the proliferation of microglial cells in ME7 mice. Analysis of the impact of the long-term treatment (4 weeks) of NBH (normal brain homogenate) or ME7 mice with control or GW2580, on the number of microglial cells. Representative pictures from the DG, with microglial cells identified by the expression of EGFP (macgreen mice; green). Scale bar 200 μm. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)CC BY · PubMed Central
Fig. 5 Gene expression screening of potential molecules regulating the pro-neurogenic activity of microglia in prion-diseased mice. (A) Progressive screening of gene expression profiles (see methods and Table S1), from microglia related mRNA species reported in two published microarray studies of models of prion disease, using whole brain (Gehlenborg et al., 2009) or hippocampal samples(Lunnon et al., 2011) and RT-PCR analysis in the dentate gyrus (DG) microdissected samples from both NBH (normal brain homogenate) and ME7 mice, at 12 and 20 weeks post-induction. Data shown colour-coding (blue to red) fold-change of prion vs. control from −9.61 to +12.81. (B) The mRNA expression of shortlisted molecular candidates (Patched, Shh, Bmp4, Bmp1r, Tgfβ1, Cntf, Igf1, Vegfa) was analysed by RT-PCR in DG microdissected samples from NBH, ME7 and ME7+GW2580 mice. Expression of mRNA represented as mean ± SEM and indicated as relative expression compared to the housekeeping gene (GAPDH) using the 2−ΔΔCT method. Statistical differences for connected bars: *p < 0.05, **p < 0.01, ***p < 0.001. Data were analysed with a one-way ANOVA showing statistical comparisons arising from a post-hoc Tukey test (n = 4).
Fig. 5 Gene expression screening of potential molecules regulating the pro-neurogenic activity of microglia in prion-diseased mice. (A) Progressive screening of gene expression profiles (see methods and Table S1), from microglia related mRNA species reported in two published microarray studies of models of prion disease, using whole brain (Gehlenborg et al., 2009) or hippocampal samples(Lunnon et al., 2011) and RT-PCR analysis in the dentate gyrus (DG) microdissected samples from both NBH (normal brain homogenate) and ME7 mice, at 12 and 20 weeks post-induction. Data shown colour-coding (blue to red) fold-change of prion vs. control from −9.61 to +12.81. (B) The mRNA expression of shortlisted molecular candidates (Patched, Shh, Bmp4, Bmp1r, Tgfβ1, Cntf, Igf1, Vegfa) was analysed by RT-PCR in DG microdissected samples from NBH, ME7 and ME7+GW2580 mice. Expression of mRNA represented as mean ± SEM and indicated as relative expression compared to the housekeeping gene (GAPDH) using the 2−ΔΔCT method. Statistical differences for connected bars: *p < 0.05, **p < 0.01, ***p < 0.001. Data were analysed with a one-way ANOVA showing statistical comparisons arising from a post-hoc Tukey test (n = 4).CC BY · PubMed Central
Fig. 6 TGFβ is responsible for the microglial pro-neurogenic activity in prion disease. (A) Immunohistochemical analysis of the localisation of TGFβ (brown) in microglial cells (Iba1+, blue) in ME7 mice. Representative examples of double-positive cells are indicated by arrowheads. (B) TGFβ mRNA expression analysed by RT-PCR in the hippocampus of NBH+AdDL70-3, NBH+AdDcn, ME7+AdDL70-3 or ME7+AdDcn mice. Expression of mRNA represented as mean ± SEM and indicated as relative expression compared to the housekeeping gene (GAPDH) using the 2−ΔΔCT method. (C) Analysis of the density of neural progenitor cells (NPCs; DCX+) at the subgranular layer (SGL) of the dentate gyrus (DG) in NBH+AdDL70-3, NBH+AdDcn, ME7+AdDL70-3 or ME7+AdDcn mice. Quantified data expressed as mean ± SEM of the number of DCX+ cells/mm2. Scale bar in (A) 50 μm. Statistical differences for connected bars: *p < 0.05. Data were analysed with a two-way ANOVA showing statistical comparisons arising from a post-hoc Tukey test (n = 4–6).
Fig. 6 TGFβ is responsible for the microglial pro-neurogenic activity in prion disease. (A) Immunohistochemical analysis of the localisation of TGFβ (brown) in microglial cells (Iba1+, blue) in ME7 mice. Representative examples of double-positive cells are indicated by arrowheads. (B) TGFβ mRNA expression analysed by RT-PCR in the hippocampus of NBH+AdDL70-3, NBH+AdDcn, ME7+AdDL70-3 or ME7+AdDcn mice. Expression of mRNA represented as mean ± SEM and indicated as relative expression compared to the housekeeping gene (GAPDH) using the 2−ΔΔCT method. (C) Analysis of the density of neural progenitor cells (NPCs; DCX+) at the subgranular layer (SGL) of the dentate gyrus (DG) in NBH+AdDL70-3, NBH+AdDcn, ME7+AdDL70-3 or ME7+AdDcn mice. Quantified data expressed as mean ± SEM of the number of DCX+ cells/mm2. Scale bar in (A) 50 μm. Statistical differences for connected bars: *p < 0.05. Data were analysed with a two-way ANOVA showing statistical comparisons arising from a post-hoc Tukey test (n = 4–6).CC BY · PubMed Central

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Metadata

Authors
De Lucia, C., Rinchon, A., Olmos-Alonso, A., Riecken, K., Fehse, B., Boche, D., Perry, V. H., & Gomez-Nicola, D.
Affiliations
  • University of Southampton (GB)
  • University Medical Center Hamburg-Eppendorf (DE)
ORCID
Venue
Brain, Behavior, and Immunity
Publisher
Elsevier BV
Published
2016-07
Volume
55
Pages
179-190
ISSN
0889-1591 (ISSN-L)
DOI
10.1016/j.bbi.2015.11.001
PMC
PMC4907582
OpenAlex
W2119211366
Cited by
110
References
58
Citations by year
2026: 4 · 2025: 7 · 2024: 11 · 2023: 9 · 2022: 10 · 2021: 15 · 2020: 17 · 2019: 10 · 2018: 7 · 2017: 12 · 2016: 8
FWCI
4.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain Behavior and Immunity (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • ORBi UMONS (submittedVersion)
Funders
  • Wessex Medical Research
  • Medical Research Council (MR/K022687/1)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
microglia, hippocampal neurogenesis, chronic neurodegeneration, prion disease, CSF1R, microglial proliferation, TGF-beta, neuronal differentiation, neurogenic niche, neuroinflammation, innate immunity
MeSH terms
Animals, Disease Models, Animal, Hippocampus, Mice, Inbred C57BL, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Transforming Growth Factor beta, Prion Diseases, Microglia, Mice, Neurogenesis

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