Microglia and the Brain: Complementary Partners in Development and Disease

Hammond, Timothy R.; Robinton, Daisy A.; Stevens, Beth

doi:10.1146/annurev-cellbio-100616-060509

Cited by 234 publications

(192 citation statements)

References 147 publications

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“…The processes and filopodia of "resting" microglia constantly engage in surveillance of the parenchyma and are critical for cell-cell interaction, sensing of chemical cues, and are involved in synapse formation and elimination 8,9,30,31 . Microglia have been described as quiescent at baseline, but their interactions with nearby neurons and astrocytes are now recognized to play important roles in the maintenance of normal brain function 7,9,32 . Upon priming and activation, microglia undergo dramatic morphological changes when they may withdraw their highly ramified processes, migrate to the sites of infections or injury in order to destroy pathogens, and remove damaged cells.…”

Section: Discussionmentioning

confidence: 99%

RiboTag-Seq Reveals a Compensatory cAMP Responsive Gene Network in Striatal Microglia Induced by Morphine Withdrawal

Coffey

Lesiak

Marx

et al. 2020

Preprint

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Microglia have recently been implicated in dependence to opioids. To investigate this directly, we used RNA sequencing of ribosome associated RNAs from striatal microglia (RiboTag-Seq) after the induction of morphine tolerance and then the precipitation of withdrawal by naloxone. We detected large, inverse changes in RNA translation following opioid tolerance and withdrawal, and bioinformatics analysis revealed an intriguing upregulation of cAMP-associated genes that are involved in microglial motility, morphology, and interactions with neurons. Three-dimensional histological reconstruction of microglia revealed changes in process branching and termination following opioid tolerance that were rapidly reversed during withdrawal and were consistent with cAMP effects on microglia morphology. Direct activation of Gicoupled DREADD receptors in microglia, rather than mimicking the effects of morphine, exacerbated opioid withdrawal. Together these indicate that microglial response to cAMP signaling can mitigate the rapid manifestations of opioid withdrawal. inverse relationship between gene expression changes duringFigure 4. Differential Expression Analysis | Naloxone administration to non-morphine-dependent animals has little effect on gene expression in the a, IP samples or d, Input samples. Morphine tolerance produces roughly equal numbers of upregulated and downregulated DEGs in both the b, IP sample and e, Input sample. Naloxone administration to morphine dependent animals produces mainly upregulation of DEGs in both the c, IP and f, Input samples. Gene expression changes during withdrawal are inversely correlated to gene expression changes during morphine tolerance in both the g, IP sample and h, Input sample.Roughly half of IP DEGs were also differentially expressed in the Input samples for both i, morphine tolerance and j, withdrawal, suggesting a common mechanism of action in neurons and microglia.

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Section: Discussionmentioning

confidence: 99%

RiboTag-Seq Reveals a Compensatory cAMP Responsive Gene Network in Striatal Microglia Induced by Morphine Withdrawal

Coffey

Lesiak

Marx

et al. 2020

Preprint

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“…This observation would imply combination therapies to be considered in the future. Bearing in mind that microglia also have beneficial aspects during chronic inflammatory processes (38)(39)(40), their pure depletion seems just temporarily advantageous. Moreover, the aggressive phagocytosis of OPCs displayed by microglia under PLX5622 may be worthwhile considering when deciding on potential complementary treatments.…”

Section: Discussionmentioning

confidence: 99%

Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion

et al. 2019

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Reduced expression of 2′‐3′‐cyclic nucleotide 3′‐phosphodiesterase (Cnp) in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by microglia ablation via colony‐stimulating factor 1 receptor (CSF1R) inhibition using PLX5622. Here we address for the first time preclinical topics crucial for translation, most importantly 1) the comparison of 2 long‐term PLX5622 applications (prevention and treatment) vs. 1 treatment alone, 2) the correlation of catatonic signs and executive dysfunction, 3) the phenotype of leftover microglia evading depletion, and 4) the role of intercellular interactions for efficient CSF1R inhibition. Based on our Cnp–/– mouse model and in vitro time‐lapse imaging, we report the unexpected discovery that microglia surviving under PLX5622 display a highly inflammatory phenotype including aggressive premortal phagocytosis of oligodendrocyte precursor cells. Interestingly, ablating microglia in vitro requires mixed glial cultures, whereas cultured pure microglia withstand PLX5622 application. Importantly, 2 extended rounds of CSF1R inhibition are not superior to 1 treatment regarding any readout investigated (magnetic resonance imaging and magnetic resonance spectroscopy, behavior, immunohistochemistry). Catatonia‐related executive dysfunction and brain atrophy of Cnp–/– mice fail to improve under PLX5622. To conclude, even though microglia depletion is temporarily beneficial and worth pursuing, complementary treatment strategies are needed for full and lasting recovery.—Fernandez Garcia‐Agudo, L., Janova, H., Sendler, L. E., Arinrad, S., Steixner, A. A., Hassouna, I., Balmuth, E., Ronnenberg, A., Schopf, N., van der Flier, F. J., Begemann, M., Martens, H., Weber, M. S., Boretius, S., Nave, K.‐A., Ehrenreich, H. Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion. FASEB J. 33, 8634–8647 (2019). http://www.fasebj.org

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“…The phagocytic activity of microglia during development is crucial in shaping neuronal networks, and dysfunction of this activity contributes to neurodevelopmental disorders 26,[58][59][60][61] .…”

Section: Discussionmentioning

confidence: 99%

“…Deficits in microglia-mediated synaptic refinement lead to dysfunctional neuronal networks and behavioral abnormalities resembling some aspects of neurodevelopmental disorders 26,[58][59][60][61] . Here, we show that n-3 PUFA deficient microglia display an altered homeostatic molecular profile at weaning with features similar to neurodegenerative microglia, previously reported as more phagocytic 92 .…”

Section: Discussionmentioning

confidence: 99%

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

Madore

Leyrolle²,

Morel

et al. 2019

Preprint

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Omega-3 fatty acids (n-3 polyunsaturated fatty acids; n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in epidemiological studies, but the mechanisms by which a n-3 PUFA dietary imbalance affects CNS development are poorly understood. Active microglial engulfment of synaptic elements is an important process for normal brain development and altered synapse refinement is a hallmark of several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development. Our results show that maternal dietary n-3 PUFA deficiency increases microglial phagocytosis of synaptic elements in the developing hippocampus, through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, which alters neuronal morphology and affects cognition in the postnatal offspring. While women of child bearing age are at higher risk of dietary n-3 PUFA deficiency, these findings provide new insights into the mechanisms linking maternal nutrition to neurodevelopmental disorders.One Sentence Summary: Low maternal omega-3 fatty acids intake impairs microgliamediated synaptic refinement via 12-HETE pathway in the developing brain.

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Microglia and the Brain: Complementary Partners in Development and Disease

Cited by 234 publications

References 147 publications

RiboTag-Seq Reveals a Compensatory cAMP Responsive Gene Network in Striatal Microglia Induced by Morphine Withdrawal

RiboTag-Seq Reveals a Compensatory cAMP Responsive Gene Network in Striatal Microglia Induced by Morphine Withdrawal

Genetically induced brain inflammation by Cnp deletion transiently benefits from microglia depletion

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

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