Light-induced engagement of microglia to focally remodel synapses in the adult brain

Cangalaya, Carla; Stoyanov, Stoyan; Fischer, Klaus–Dieter; Dityatev, Alexander

doi:10.7554/elife.58435

Cited by 31 publications

(24 citation statements)

References 48 publications

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“…All animal experiments were conducted in accordance with ethical animal research standards defined by the Directive 2010/63/EU, the German law and the recommendations of the Ethical Committee on Animal Health and Care of the State of Saxony-Anhalt, Germany (license number: 42502-2-1346). Eight male Cx3cr1Cre/Tomato x GFPM Thy-1 mice, which expressed red fluorescent protein (tdTomato) in all microglial cells and enhanced green fluorescent protein (EGFP) in a subset of cortical pyramidal neurons, were used in the study as described previously [20]. Animals were housed individually under standard conditions, including ad libitum access to food and water and a 12 h light/12 h dark cycle.…”

Section: Animalsmentioning

confidence: 99%

“…The animals were treated according to the previously published protocol [20]. To induce the recombination that labels microglia with the red fluorescent protein tdTomato, all mice were injected intraperitoneally with tamoxifen at a concentration of 100 mg/kg of body weight at P30 for 5 consecutive days [25].…”

Section: Plx 3397 Treatmentmentioning

confidence: 99%

“…Microglia perform surveillance of their surroundings with their long and versatile processes monitoring synapses and eliminate some synaptic components. This non-cellautonomous mechanism of synaptic remodeling is still under investigation but suggests a key role for microglia in diverse forms of synaptic plasticity [20]. For their survival, microglia highly depend on the colony-stimulating factor 1 (CSF1) signaling pathway [21].…”

Section: Introductionmentioning

confidence: 99%

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Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice

Strackeljan

Bączyńska

Cangalaya

et al. 2021

Cells

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The extracellular matrix (ECM) plays a key role in synaptogenesis and the regulation of synaptic functions in the central nervous system. Recent studies revealed that in addition to dopaminergic and serotoninergic neuromodulatory systems, microglia also contribute to the regulation of ECM remodeling. In the present work, we investigated the physiological role of microglia in the remodeling of perineuronal nets (PNNs), predominantly associated with parvalbumin-immunopositive (PV+) interneurons, and the perisynaptic ECM around pyramidal neurons in the hippocampus. Adult mice were treated with PLX3397 (pexidartinib), as the inhibitor of colony-stimulating factor 1 receptor (CSF1-R), to deplete microglia. Then, confocal analysis of the ECM and synapses was performed. Although the elimination of microglia did not alter the overall number or intensity of PNNs in the CA1 region of the hippocampus, it decreased the size of PNN holes and elevated the expression of the surrounding ECM. In the neuropil area in the CA1 str. radiatum, the depletion of microglia increased the expression of perisynaptic ECM proteoglycan brevican, which was accompanied by the elevated expression of presynaptic marker vGluT1 and the increased density of dendritic spines. Thus, microglia regulate the homeostasis of pre- and postsynaptic excitatory terminals and the surrounding perisynaptic ECM as well as the fine structure of PNNs enveloping perisomatic—predominantly GABAergic—synapses.

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Section: Animalsmentioning

confidence: 99%

Section: Plx 3397 Treatmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice

Strackeljan

Bączyńska

Cangalaya

et al. 2021

Cells

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“…Microglial maturation, in turn, is regulated by other immune cells 63 . Microglial cells play principle role in rapidly promoting spine turnover after synaptic photodamage 221 and protecting neurons from stroke‐induced brain damage 71 . Microglia‐neuron interactions are regulated by a number of intracellular checkpoints and receptor‐mediated mechanisms 222 …”

Section: Microglial Interactions With Other Cns Cell Typesmentioning

confidence: 99%

Microglia‐leucocyte axis in cerebral ischaemia and inflammation in the developing brain

2021

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Development of the Central Nervous System (CNS) is reliant on the proper function of numerous intricately orchestrated mechanisms that mature independently, including constant communication between the CNS and the peripheral immune system. This review summarizes experimental knowledge of how cerebral ischaemia in infants and children alters physiological communication between leucocytes, brain immune cells, microglia and the neurovascular unit (NVU)—the “microglia‐leucocyte axis”—and contributes to acute and long‐term brain injury. We outline physiological development of CNS barriers in relation to microglial and leucocyte maturation and the plethora of mechanisms by which microglia and peripheral leucocytes communicate during postnatal period, including receptor‐mediated and intracellular inflammatory signalling, lipids, soluble factors and extracellular vesicles. We focus on the “microglia‐leucocyte axis” in rodent models of most common ischaemic brain diseases in the at‐term infants, hypoxic‐ischaemic encephalopathy (HIE) and focal arterial stroke and discuss commonalities and distinctions of immune‐neurovascular mechanisms in neonatal and childhood stroke compared to stroke in adults. Given that hypoxic and ischaemic brain damage involve Toll‐like receptor (TLR) activation, we discuss the modulatory role of viral and bacterial TLR2/3/4‐mediated infection in HIE, perinatal and childhood stroke. Furthermore, we provide perspective of the dynamics and contribution of the axis in cerebral ischaemia depending on the CNS maturational stage at the time of insult, and modulation independently and in consort by individual axis components and in a sex dependent ways. Improved understanding on how to modify crosstalk between microglia and leucocytes will aid in developing age‐appropriate therapies for infants and children who suffered cerebral ischaemia.

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“…During inflammatory events, microglial cells alter their function to attempt restoring homeostasis, which includes secretion of cytokines, endocytosis, and engulfment of debris. These inflammatory-related functions may drastically impact synaptic function by the secretion of factors that modify LTP/LTD (Zhou et al, 2019 ), degradation of extracellular matrix components inherent to the synaptic cleft (Tremblay et al, 2010 ; Nguyen et al, 2020 ), engulfment of synaptic terminals (Perry and O’Connor, 2010 ), and reshaping of dendrites (Cangalaya et al, 2020 ). An important arm of the inflammatory response in the brain is the infiltration of complement-related proteins, which have been shown to actively participate in synapse elimination (Stevens et al, 2007 ).…”

Section: Inflammation As a Contributor To Synaptic Failure In Lsdsmentioning

confidence: 99%

Synaptic Function and Dysfunction in Lysosomal Storage Diseases

Rebiai

Givogri

Gowrishankar

et al. 2021

Front. Cell. Neurosci.

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Lysosomal storage diseases (LSDs) with neurological involvement are inherited genetic diseases of the metabolism characterized by lysosomal dysfunction and the accumulation of undegraded substrates altering glial and neuronal function. Often, patients with neurological manifestations present with damage to the gray and white matter and irreversible neuronal decline. The use of animal models of LSDs has greatly facilitated studying and identifying potential mechanisms of neuronal dysfunction, including alterations in availability and function of synaptic proteins, modifications of membrane structure, deficits in docking, exocytosis, recycling of synaptic vesicles, and inflammation-mediated remodeling of synapses. Although some extrapolations from findings in adult-onset conditions such as Alzheimer’s disease or Parkinson’s disease have been reported, the pathogenetic mechanisms underpinning cognitive deficits in LSDs are still largely unclear. Without being fully inclusive, the goal of this mini-review is to present a discussion on possible mechanisms leading to synaptic dysfunction in LSDs.

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Light-induced engagement of microglia to focally remodel synapses in the adult brain

Cited by 31 publications

References 48 publications

Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice

Microglia Depletion-Induced Remodeling of Extracellular Matrix and Excitatory Synapses in the Hippocampus of Adult Mice

Microglia‐leucocyte axis in cerebral ischaemia and inflammation in the developing brain

Synaptic Function and Dysfunction in Lysosomal Storage Diseases

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