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1.
Nature ; 586(7829): 417-423, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32999463

RESUMO

Microglia, the brain's resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival1. Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A1R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease.


Assuntos
Retroalimentação Fisiológica , Microglia/fisiologia , Inibição Neural , Neurônios/fisiologia , 5'-Nucleotidase/metabolismo , Potenciais de Ação , Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antígenos CD/metabolismo , Apirase/metabolismo , Cálcio/metabolismo , Corpo Estriado/citologia , Corpo Estriado/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Inibição Neural/genética , Receptor A1 de Adenosina/metabolismo , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Fatores de Tempo
2.
Neuropathology ; 39(3): 173-180, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31131941

RESUMO

Microglia, the sole immune cells in the brain, are the key player for synaptic regulation required for our brain function in both developing and adult brain. They have highly motile processes to detect synaptic functions. Recent accumulated studies have unveiled the mechanism underlying synapse detection and pruning / formation by microglia. In this review, we summarize the current knowledge of various microglial machinery recruited in synaptic modulation in the different life stages and contexts.


Assuntos
Encéfalo/fisiologia , Microglia/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Encéfalo/citologia , Humanos , Rede Nervosa/citologia , Sinapses/fisiologia
3.
Nagoya J Med Sci ; 85(4): 772-778, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38155622

RESUMO

Microglial processes survey the brain parenchyma, but it is unknown whether this process is influenced by the cell activity of nearby microglia under physiological conditions. Herein, we showed that microglial process dynamics differ when facilitated by astrocytic activity and pre-synaptic activity. The results revealed distinct microglial process dynamics associated with the activity of other brain cells.


Assuntos
Astrócitos , Microglia , Humanos , Microglia/fisiologia , Encéfalo
4.
Brain Nerve ; 73(8): 913-919, 2021 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-34376598

RESUMO

The central nervous system (CNS) is an immune-privileged area. The blood-brain barrier (BBB) is thought to separate the CNS from any systemic inflammatory states to maintain homeostasis within this specialized, vulnerable organ. However, accumulating studies have challenged this concept by demonstrating systemic inflammatory effects on brain. Moreover, the coronavirus disease pandemic caused by severe acute respiratory syndrome coronavirus 2 in 2019 has rapidly evoked attention toward the BBB as the systemic-CNS immunological interface. In this review, we focus on microglia, the sole immune cells in the CNS, and briefly introduce our new findings regarding microglial BBB regulation in systemic inflammation. With a close eye on associated literature, we carefully rethink the traditional immune system in the CNS and suggest a new possible mechanism of systemic-CNS immune cell interaction, while an understanding of the BBB develops.


Assuntos
Barreira Hematoencefálica , COVID-19 , Encéfalo , Humanos , Microglia , SARS-CoV-2
5.
Sci Rep ; 10(1): 21378, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288794

RESUMO

Maternal infection or inflammation causes abnormalities in brain development associated with subsequent cognitive impairment and in an increased susceptibility to schizophrenia and autism spectrum disorders. Maternal immune activation (MIA) and increases in serum cytokine levels mediates this association via effects on the fetal brain, and microglia can respond to maternal immune status, but consensus on how microglia may respond is lacking and no-one has yet examined if microglial process motility is impaired. In this study we investigated how MIA induced at two different gestational ages affected microglial properties at different developmental stages. Immune activation in mid-pregnancy increased IL-6 expression in embryonic microglia, but failed to cause any marked changes in morphology either at E18 or postnatally. In contrast MIA, particularly when induced earlier (at E12), caused sustained alterations in the patterns of microglial process motility and behavioral deficits. Our research has identified an important microglial property that is altered by MIA and which may contribute to the underlying pathophysiological mechanisms linking maternal immune status to subsequent risks for cognitive disease.


Assuntos
Feto/citologia , Feto/metabolismo , Microglia/citologia , Microglia/fisiologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Modelos Animais de Doenças , Feminino , Inflamação/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal
6.
Methods Mol Biol ; 2034: 281-286, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31392692

RESUMO

Microglia are traditionally known as immune sentinels of the brain and as key player in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, or amyotrophic lateral sclerosis. Recently, they were also identified as synaptic organizer, promoting formation and maturation of synapses as well as modifying synaptic activity. Interestingly, microglia-mediated synaptic pruning and microglia-mediated changes in synaptic plasticity were observed both during brain development and in neurodegenerative diseases, stressing the key role of microglia-synapse interaction in these processes. Here we descried a technique for noninvasive in vivo monitoring of microglia-synapse interactions by means of two-photon microscopy.


Assuntos
Encéfalo , Microglia , Microscopia de Fluorescência por Excitação Multifotônica , Doenças Neurodegenerativas , Plasticidade Neuronal/genética , Sinapses , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Sinapses/genética , Sinapses/metabolismo , Sinapses/patologia
7.
Nat Commun ; 10(1): 5816, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31862977

RESUMO

Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.


Assuntos
Barreira Hematoencefálica/metabolismo , Circulação Cerebrovascular/imunologia , Células Endoteliais/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Microglia/imunologia , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/imunologia , Claudina-5/imunologia , Claudina-5/metabolismo , Modelos Animais de Doenças , Células Endoteliais/imunologia , Humanos , Microscopia Intravital , Masculino , Camundongos , Microglia/metabolismo , Permeabilidade , Fagocitose/imunologia , Receptores CCR5/imunologia , Receptores CCR5/metabolismo , Técnicas Estereotáxicas , Junções Íntimas/imunologia , Junções Íntimas/metabolismo
8.
eNeuro ; 5(5)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30406198

RESUMO

Microglia are highly motile immunoreactive cells that play integral roles in the response to brain infection and damage, and in the progression of various neurological diseases. During development, microglia also help sculpt neural circuits, via both promoting synapse formation and by targeting specific synapses for elimination and phagocytosis. Microglia are also active surveyors of neural circuits in the mature, healthy brain, although the functional consequences of such microglia-neuron contacts under these conditions is unclear. Using in vivo imaging of neurons and microglia in awake mice, we report here the functional consequences of microglia-synapse contacts. Direct contact between a microglial process and a single synapse results in a specific increase in the activity of that contacted synapse, and a corresponding increase in back-propagating action potentials along the parent dendrite. This increase in activity is not seen for microglia-synapse contacts when microglia are activated by chronic lipopolysaccharide (LPS) treatment. To probe how this microglia-synapse contact affects neural circuits, we imaged across larger populations of motor cortical neurons. When microglia were again activated by LPS (or partially ablated), there was a decrease in the extent to which neuronal activity was synchronized. Together, our results demonstrate that interactions between physiological or resting microglia and synapses in the mature, healthy brain leads to an increase in neuronal activity and thereby helps to synchronize local populations of neurons. Our novel findings provide a plausible physical basis for understanding how alterations in immune status may impact on neural circuit plasticity and on cognitive behaviors such as learning.


Assuntos
Encéfalo/fisiologia , Microglia/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Animais , Dendritos/fisiologia , Aprendizagem/fisiologia , Camundongos Transgênicos , Neurogênese/fisiologia , Neurônios/fisiologia
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