Microglia control the glycinergic but not the GABAergic synapses via prostaglandin E2 in the spinal cord

Cantaut-Belarif, Yasmine; Antri, Myriam; Pizzarelli, Rocco; Colasse, Sabrina; Vaccari, I.; Soares, Sylvia; Renner, Marianne; Dallel, Radhouane; Triller, Antoine; Bessis, Alain

doi:10.1083/jcb.201607048

Cited by 54 publications

(43 citation statements)

References 65 publications

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“…The higher PPR, together with the higher failure rate observed under conditions of minimal stimulation, strongly argues for a reduction in the probability of transmitter release in KO mice (Stevens & Wang, ). Moreover, our results in the minimal stimulation paradigm, showing that the potency is normal in KO synapses, and the previously reported similar mEPSC amplitudes in WT and KO (Zhan et al, ) argue against a postsynaptic mechanism, like those reported previously (Cantaut‐Belarif et al, ; Ragozzino et al, ). In addition, we found no differences in the increase in potency, typically seen at high release probability, suggesting that the number of release sites or vesicles is unchanged in the KO (Isaac et al, ; Stevens & Wang, ).…”

Section: Discussionsupporting

confidence: 89%

“…Although we cannot entirely rule out more complicated mechanisms, including the above mentioned presence of subpopulations of synapses contributing preferentially to the KO deficit under different conditions of stimulation, we favor the interpretation that the KO phenotype is primarily the result of a presynaptic maturation deficit. In contrast, an intriguing way to explain our results, would be that synapses continuously need microglia interaction (by contact or soluble factors) for their correct functioning (Cantaut‐Belarif et al, ; Parkhurst et al, ). Further studies will be necessary to understand the cellular and molecular mechanisms underlying the specific effect of microglia on presynaptic function and to determine whether similar processes are important in the development of other brain structures and in synaptic plasticity during normal and pathological states in adulthood (Parkhurst et al, ; Schafer et al, ).…”

Section: Discussionmentioning

confidence: 81%

“…In contrast, an intriguing way to explain our results, would be that synapses continuously need microglia interaction (by contact or soluble factors) for their correct functioning (Cantaut-Belarif et al, 2017;Parkhurst et al, 2013). Further studies will be necessary to understand the cellular and molecular mechanisms underlying the specific effect of microglia on presynaptic function and to determine whether similar processes are important in the development of other brain structures and in synaptic plasticity during normal and pathological states in adulthood (Parkhurst et al, 2013;Schafer et al, 2012).…”

Section: Discussionmentioning

confidence: 91%

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Microglia shape presynaptic properties at developing glutamatergic synapses

Basilico

Pagani

Grimaldi

et al. 2018

Glia

114

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Deficient neuron–microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron‐to‐microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission. We characterized the functional properties of CA3–CA1 synapses in hippocampal slices from these mice and found that they display altered glutamatergic release probability, maintaining immature properties also at late developmental stages. In particular, CA1 synapses of Cx3cr1 KO show (i) immature AMPA/NMDA ratio across developmental time, displaying a normal NMDA component and a defective AMPA component of EPSC; (ii) defective functional connectivity, as demonstrated by reduced current amplitudes in the input/output curve; and (iii) greater facilitation in the paired pulse ratio (PPR), suggesting decreased release probability. In addition, minimal stimulation experiments revealed that excitatory synapses have normal potency, but an increased number of failures, confirming a deficit in presynaptic release. Consistently, KO mice were characterized by higher number of silent synapses in comparison to WT. The presynaptic deficits were corrected by performing experiments in conditions of high release probability (Ca2+/Mg2+ratio 8), where excitatory synapses showed normal synaptic multiplicity, AMPA/NMDA ratio, and proportion of silent synapses. These results establish that neuron–microglia interactions profoundly influence the functional maturation of excitatory presynaptic function.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 91%

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Microglia shape presynaptic properties at developing glutamatergic synapses

Basilico

Pagani

Grimaldi

et al. 2018

Glia

114

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“…This demonstration adds one more line of evidence to the emerging theme of microglia as a modulator of neurotransmission (Cantaut-Belarif et al, 2017;Marrone et al, 2017). Intranasal administration of an NGF variant was recently proven to be highly neuroprotective in an AD mouse model: 53FAD mice chronically treated with the neurotrophin showed a dramatic reduction of the plaque load, with a clear evidence of the involvement of microglial cells in the clearance of Ab (Capsoni et al, 2017).…”

Section: Discussionmentioning

confidence: 71%

NGF steers microglia toward a neuroprotective phenotype

Rizzi

Tiberi

Giustizieri

et al. 2018

Glia

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Microglia are the sentinels of the brain but a clear understanding of the factors that modulate their activation in physiological and pathological conditions is still lacking. Here we demonstrate that Nerve Growth Factor (NGF) acts on microglia by steering them toward a neuroprotective and anti‐inflammatory phenotype. We show that microglial cells express functional NGF receptors in vitro and ex vivo. Our transcriptomic analysis reveals how, in primary microglia, NGF treatment leads to a modulation of motility, phagocytosis and degradation pathways. At the functional level, NGF induces an increase in membrane dynamics and macropinocytosis and, in vivo, it activates an outward rectifying current that appears to modulate glutamatergic neurotransmission in nearby neurons. Since microglia are supposed to be a major player in Aβ peptide clearance in the brain, we tested the effects of NGF on its phagocytosis. NGF was shown to promote TrkA‐mediated engulfment of Aβ by microglia, and to enhance its degradation. Additionally, the proinflammatory activation induced by Aβ treatment is counteracted by the concomitant administration of NGF. Moreover, by acting specifically on microglia, NGF protects neurons from the Aβ‐induced loss of dendritic spines and inhibition of long term potentiation. Finally, in an ex‐vivo setup of acute brain slices, we observed a similar increase in Aβ engulfment by microglial cells under the influence of NGF. Our work substantiates a role for NGF in the regulation of microglial homeostatic activities and points toward this neurotrophin as a neuroprotective agent in Aβ accumulation pathologies, via its anti‐inflammatory activity on microglia.

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“…In addition to the complement‐mediated mechanism, astrocyte‐derived interleukin (IL)‐33 is also physiologically required to maintain synapse homeostasis by modulating microglial synapse engulfment (Vainchtein et al, ). Microglia are involved in regulating and shaping both excitatory and inhibitory synapses, such as γ‐aminobutyric acid‐expressing and glycinergic synapses (Cantaut‐Belarif et al, ; Um, ). Conversely, early evidence obtained from CX3CR1 gene‐deleted mice indicated that reduced numbers of microglial cells during brain development could impair the processes of synaptic pruning, resulting in a significantly higher density of dendritic spines and immature synapses (Paolicelli et al, ; Shibata & Suzuki, ).…”

Section: Multi‐tasking Microglia: a Friend For Brain Homeostasismentioning

confidence: 99%

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

Han

Zhu

Zhang

et al. 2018

Glia

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Microglia are prominent immune cells in the central nervous system (CNS) and are critical players in both neurological development and homeostasis, and in neurological diseases when dysfunctional. Our previous understanding of the phenotypes and functions of microglia has been greatly extended by a dearth of recent investigations. Distinct genetically defined subsets of microglia are now recognized to perform their own independent functions in specific conditions. The molecular profiling of single microglial cells indicates extensively heterogeneous reactions in different neurological disorders, resulting in multiple potentials for crosstalk with other kinds of CNS cells such as astrocytes and neurons. In settings of neurological diseases it could thus be prudent to establish effective cell‐based therapies by targeting entire microglial networks. Notably, activated microglial depletion through genetic targeting or pharmacological therapies within a suitable time window can stimulate replenishment of the CNS niche with new microglia. Additionally, enforced repopulation through provision of replacement cells also represents a potential means of exchanging dysfunctional with functional microglia. In each setting the newly repopulated microglia might have the potential to resolve ongoing neuroinflammation. In this review, we aim to summarize the most recent knowledge of microglia and to highlight microglial depletion and subsequent repopulation as a promising cell replacement therapy. Although glial cell replacement therapy is still in its infancy and future translational studies are still required, the approach is scientifically sound and provides new optimism for managing the neurotoxicity and neuroinflammation induced by activated microglia.

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Microglia control the glycinergic but not the GABAergic synapses via prostaglandin E2 in the spinal cord

Cited by 54 publications

References 65 publications

Microglia shape presynaptic properties at developing glutamatergic synapses

Microglia shape presynaptic properties at developing glutamatergic synapses

NGF steers microglia toward a neuroprotective phenotype

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

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