Microglia-mediated synaptic pruning is impaired in sleep-deprived adolescent mice

Tuan, Li‐Heng; Lee, Li-Jen

doi:10.1016/j.nbd.2019.104517

Cited by 74 publications

(49 citation statements)

References 109 publications

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“…In parallel, an increased density of excitatory synapses and reduced CD68 expression was observed. This was associated with reduced engulfment of postsynaptic density by microglia in adolescence but not in adulthood [76]. Chronic social isolation starting at weaning induced an increase in the expression of IBA-1 and CD11b and a decrease in CD200R mRNA in the HIP of rats, along with neuronal epigenetic alterations that were rescued by poststress minocycline treatment [74].…”

Section: Effects Of Postnatal-stress-induced Microglial Alterations Omentioning

confidence: 93%

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

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Section: Effects Of Postnatal-stress-induced Microglial Alterations Omentioning

confidence: 93%

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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“…Z‐stacks of fluorescent images containing individual Iba1‐positive microglia in the striatum were acquired with a confocal microscope (LSM880, Zeiss, Jena, Germany) at 63x magnification with a 1.5× digital zoom using a z‐step of 0.6 μm (Tuan & Lee, ). The background signals of all fluorescence channels were subtracted by ImageJ (NIH).…”

Section: Methodsmentioning

confidence: 99%

“…Amphetamine (Amph) is known to produce psychosis similar to that in patients with schizophrenia (Bell, 1973;Janowsky & Risch, 1979) and worsen the symptoms of schizophrenia (Laruelle, Abi-Dargham, Gil, Kegeles, & Innis, 1999). Reaction to Amph challenge is therefore commonly tested in animal models of schizophrenia (van den Buuse, Garner, Gogos, & Kusljic, 2005). Immediately after Amph injection, mice of both genotypes exhibited increased locomotor activity that lasted for more than 120 min.…”

Section: Western Blot Analysismentioning

confidence: 99%

Characterization of striatal phenotypes in heterozygous Disc1 mutant mice, a model of haploinsufficiency

Baskaran

Lai

et al. 2019

J of Comparative Neurology

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Disrupted‐in‐Schizophrenia 1 (DISC1) is a susceptibility gene for several psychiatric illnesses. To study the pathogenesis of these disorders, we generated Disc1 mutant mice by introducing the 129S6/SvEv 25‐bp deletion Disc1 variants into the C57BL/6J strain. In this study, we used heterozygous Disc1 mutant (Het) mice to evaluate the DISC1 haploinsufficiency model of schizophrenia. No changes in locomotor behaviors were observed in Het mice; however, after amphetamine injection, greater locomotor activity was observed in Het mice compared with wild‐type (WT) mice. Moreover, amphetamine‐induced elevations of c‐Fos expression and dopamine level in the striatum were greater in Het mice than in WT controls, suggesting an altered dopaminergic regulation in the striatum of Het mice. Compared with those in WTs, the striatal protein levels of dopamine transporter and D2 dopamine receptor were increased in Het mice, while D1 dopamine receptor level was decreased. DISC1 interacting proteins, GSK3α and GSK3β, were downregulated in Het mice, whereas the levels of PDE4B and CREB were not altered. Morphologically, the complexities of striatal median spiny neurons (MSNs), parvalbumin‐positive interneurons and Iba1‐positive microglia were all decreased in Het mice. The density and head diameter of dendritic spines in the MSNs of Het mice were also reduced. Our results indicate that mice lacking one WT Disc1 allele are more sensitive to psychostimulant amphetamine challenge, which might be attributed to the altered structure and function of the striatal dopaminergic system. Here, we demonstrated striatal phenotypes in heterozygous Disc1 mutant mice, which could be a promising model of DISC1 haploinsufficiency.

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“…P2Y 12 R is also implicated in synaptic pruning via modulating microglial phagocytosis. Recent work shows that sleep deprivation disrupted the process of synapse elimination and complement signaling with reduced expression of P2Y 12 R in adolescent but not in adult (Tuan & Lee., ). Interestingly, transcription of P2Y 12 R in microglia depends on Bmal1 and circadian‐driven expression of P2Y 12 R controls diurnal morphological changes in cortical microglia (Hayashi, ).…”

Section: Introductionmentioning

confidence: 97%

“…Recent work shows that sleep deprivation disrupted the process of synapse elimination and complement signaling with reduced expression of P2Y 12 R in adolescent but not in adult (Tuan & Lee., 2019).…”

mentioning

confidence: 99%

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

et al. 2019

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A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid‐beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV‐ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1‐42 (fAβ1‐42) than at CT12. BMAL1 directly drives transcription of REV‐ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV‐ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV‐ERBs‐accelerated microglial uptake of fAβ1‐42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2‐like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev‐erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque‐associated increases in disease‐associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV‐ERBs and provides new insights into the role of REV‐ERBs in AD.

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Microglia-mediated synaptic pruning is impaired in sleep-deprived adolescent mice

Cited by 74 publications

References 109 publications

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Characterization of striatal phenotypes in heterozygous Disc1 mutant mice, a model of haploinsufficiency

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

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