A decade of diverse microglial-neuronal physical interactions in the brain (2008–2018)

Uweru, Joseph O.; Eyo, Ukpong B.

doi:10.1016/j.neulet.2019.01.001

Cited by 12 publications

(5 citation statements)

References 74 publications

(96 reference statements)

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“…Our data are consistent with previous studies revealing microglial processes in contact with different subcellular compartments of neurons (Uweru & Eyo, 2019) and can be important for bidirectional functional interactions between microglia and interneurons in continuously changing brain environment. In this partnership, microglia can sense fluctuations in ion concentrations, signaling molecules and neurotransmitters at the sites of synaptic contacts and during high neuronal activity.…”

Section: Discussionsupporting

confidence: 93%

“…(e) Correlation between the area of interaction and the distance from the interneuron soma for SOM+ (left) and PV+ interneurons (right) (SOM+ cells: r = 0.0598; p = .791; Pearson's correlation test; n = 44 interneurons/17 slices/three mice; PV+ cells: r = 0.1575; p = .145; Pearson's correlation test; n = 25 interneurons/23 slices/three mice). Insets show the distributions for total dendritic length of corresponding interneuron types neurons(Uweru & Eyo, 2019) and can be important for bidirectional functional interactions between microglia and interneurons in continuously changing brain environment. In this partnership, microglia can sense fluctuations in ion concentrations, signaling molecules and neurotransmitters at the sites of synaptic contacts and during high neuronal activity.…”

mentioning

confidence: 99%

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Structural analysis of the microglia–interneuron interactions in the CA1 hippocampal area of the APP/PS1 mouse model of Alzheimer's disease

Gervais

Iloun

Martianova

et al. 2021

J of Comparative Neurology

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Microglia can interact with glutamatergic neurons and, through control of synaptic elements, regulate their physiological function. Much less is known about the partnership between microglia and GABAergic inhibitory interneurons. Here, we compared the interactions between microglia and parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the CA1 hippocampal area of APP/PS1 transgenic mice that mimic certain aspects of the Alzheimer's disease (AD). We first uncovered a high level of interactions between microglia and two types of interneurons, with 98% of SOM+ and 90% of PV+ cells receiving different types of putative microglial contacts. The latter included the microglia soma to the interneuron soma (SomaMG‐to‐SomaIN), the microglia process to the interneuron soma (ProcessMG‐to‐SomaIN) and the microglia process to the interneuron dendrite (ProcessMG‐to‐DendIN) interactions. Moreover, we found significantly larger areas of interaction for the SomaMG‐to‐SomaIN and the ProcessMG‐to‐DendIN type of contacts between microglia and SOM+ cells. In contrast, PV+ cells exhibited larger areas for the ProcessMG‐to‐SomaIN interactions. Second, in APP/PS1 mice, although the overall microglia interactions with interneurons remained preserved, the fraction of interneurons receiving putative microglia contacts on their dendrites was reduced, and larger areas of interactions were observed for somatic contacts, suggesting a stronger modulation of the interneuron output by microglia in AD. In summary, these results reveal microglia as important partners of hippocampal PV+ and SOM+ GABAergic cells, with interneuron type‐specific pattern of interactions. Thus, microglia may play an essential role in the operation of interneurons under normal conditions and their dysfunction in disease.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Structural analysis of the microglia–interneuron interactions in the CA1 hippocampal area of the APP/PS1 mouse model of Alzheimer's disease

Gervais

Iloun

Martianova

et al. 2021

J of Comparative Neurology

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“…Microglia are known to play a major role in synaptic removal and plasticity, notably via phagocytosis in healthy and disease states [20,46]. To determine the functional implications of the decreased morphological indices we observed in R6/2 mice, we investigated the phagocytic index in microglia by measuring levels of CD68, a transmembrane protein highly expressed by microglia and macrophages that is enriched in their phagolysosomal compartments [47].…”

Section: Resultsmentioning

confidence: 99%

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington's disease pathology

Savage

St‐Pierre

Carrier

et al. 2019

Preprint

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Background: Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain's resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD.Methods: To provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10 and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam-scanning electron microscopy.Results: At 3 weeks of age, prior to any known motor deficits, light microscopy studies revealed that microglia in R6/2 animals displayed a mature morphological phenotype, not reached by microglia in WT animals until 7-10 weeks of age. Microglia from R6/2 mice across all ages investigated also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week old R6/2 mice made fewer contacts with synaptic structures than those of 3-week old R6/2 mice and age-matched WT littermates. While synaptic density was not affected by genotype at 3 weeks of age, it only increased with maturation in WT mice between 3 and 10 weeks of age. The location of synapses was lastly modified from targeting dendritic spines to trunks at 3 and 10 weeks of age in R6/2 mice versus WT controls.Conclusions: These findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.

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“…Microglia are known to play a major role in synaptic removal and plasticity, notably via phagocytosis in healthy and disease states [20,54]. To determine the functional implications of the decreased morphological indices in R6/2 mice, we quantified the immunolabeling for CD68, a transmembrane protein highly expressed by microglia and macrophages that is enriched in their phagolysosomal compartments [55].…”

Section: Microglial Phagocytosis Is Increased In the R6/2 Mouse Modelmentioning

confidence: 99%

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington’s disease pathology

Savage

St‐Pierre

Carrier

et al. 2020

J Neuroinflammation

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Background: Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder that affects cognitive and motor abilities by primarily targeting the striatum and cerebral cortex. HD is caused by a mutation elongating the CAG repeats within the Huntingtin gene, resulting in HTT protein misfolding. Although the genetic cause of HD has been established, the specific susceptibility of neurons within various brain structures has remained elusive. Microglia, which are the brain's resident macrophages, have emerged as important players in neurodegeneration. Nevertheless, few studies have examined their implication in HD. Methods: To provide novel insights, we investigated the maturation and dysfunction of striatal microglia using the R6/2 mouse model of HD. This transgenic model, which presents with 120+/-5 CAG repeats, displays progressive motor deficits beginning at 6 weeks of age, with full incapacitation by 13 weeks. We studied microglial morphology, phagocytic capacity, and synaptic contacts in the striatum of R6/2 versus wild-type (WT) littermates at 3, 10, and 13 weeks of age, using a combination of light and transmission electron microscopy. We also reconstructed dendrites and determined synaptic density within the striatum of R6/2 and WT littermates, at nanoscale resolution using focused ion beam scanning electron microscopy. Results: At 3 weeks of age, prior to any known motor deficits, microglia in R6/2 animals displayed a more mature morphological phenotype than WT animals. Microglia from R6/2 mice across all ages also demonstrated increased phagocytosis, as revealed by light microscopy and transmission electron microscopy. Furthermore, microglial processes from 10-week-old R6/2 mice made fewer contacts with synaptic structures than microglial processes in 3week-old R6/2 mice and age-matched WT littermates. Synaptic density was not affected by genotype at 3 weeks of age but increased with maturation in WT mice. The location of synapses was lastly modified in R6/2 mice compared with WT controls, from targeting dendritic spines to dendritic trunks at both 3 and 10 weeks of age. Conclusions: These findings suggest that microglia may play an intimate role in synaptic alteration and loss during HD pathogenesis.

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A decade of diverse microglial-neuronal physical interactions in the brain (2008–2018)

Cited by 12 publications

References 74 publications

Structural analysis of the microglia–interneuron interactions in the CA1 hippocampal area of the APP/PS1 mouse model of Alzheimer's disease

Structural analysis of the microglia–interneuron interactions in the CA1 hippocampal area of the APP/PS1 mouse model of Alzheimer's disease

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington's disease pathology

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington’s disease pathology

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