Pruning hypothesis comes of age

Johnson, Matthew B.; Stevens, Beth

doi:10.1038/d41586-018-02053-7

Cited by 38 publications

(30 citation statements)

References 14 publications

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“…Microglia, resident macrophages in brain, respond to local in ammation or CNS damage by becoming reactive, increasing phagocytic activity and in ammatory cytokine production 35 . To determine whether microglial activation participates in NPSLE development, we assessed the active state of microglia via cell morphology and density in MRL/lpr mouse brains during the early (6-8 weeks) and active (16)(17)(18)(19)(20) weeks) stages of SLE. As noted, in addition to increased IBA-1 + cell numbers ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Elimination of synapses has been observed in Alzheimer's disease (AD) 16 and during aging 17 and is central to the neurodegenerative process. The engulfment of dendritic processes by activated microglia 18 , the resident macrophages of the CNS, represents one potential mechanism for this phenomenon. Microglia-mediated synapse pruning is implicated in normal brain development 19,20 and might be reactivated in the diseased brain 21 .…”

Section: Introductionmentioning

confidence: 99%

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Neuronal NR4A1 and complement coordinate synaptic stripping by microglia in lupus

Han¹,

Xu²,

Fang³

et al. 2020

Preprint

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Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Here we showed that complement-coordinated elimination of synapses participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We demonstrated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. In lupus brain, C1q was increased and localized at synaptic terminals, causing the apposition of phagocytic microglia, ensuing synaptic loss, and neurological disease. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition and then apposition of phagocytic microglia, resulting in synaptic loss and neurological disease. Minocycline-deactivated microglia, antibody-blocked C1q, or neuronal Nr4a1 restored protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlight neuronal Nr4a1 and C1q as critical components amenable to pharmacological intervention in NPSLE.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neuronal NR4A1 and complement coordinate synaptic stripping by microglia in lupus

Han¹,

Xu²,

Fang³

et al. 2020

Preprint

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“…An eQTL study in post‐mortem human brain tissue demonstrated that increasing copy number of C4A and C4B was associated with increased expression of each of these genes . Interestingly, C4 acts within the complement cascade involved in synaptic pruning, a process thought to be aberrant in schizophrenia . Such synaptic pruning deficits may explain neuroimaging findings showing an accelerated loss of frontal grey matter in schizophrenia patients .…”

Section: A Causal Pathway By Which Genetic Variation Impacts Risk Formentioning

confidence: 99%

“…50 Interestingly, C4 acts within the complement cascade involved in synaptic pruning, a process thought to be aberrant in schizophrenia. 51,52 Such synaptic pruning deficits may explain neuroimaging findings showing an accelerated loss of frontal grey matter in schizophrenia patients. 53 Does modulation of C4 expression impact synaptic pruning?…”

Section: A Causal Pathway By Which Genetic Variation Impacts Risk Formentioning

confidence: 99%

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

Stein

2019

Psychiatry Clin Neurosci

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Imaging genetics aims to identify genetic variants associated with the structure and function of the human brain. Recently, collaborative consortia have been successful in this goal, identifying and replicating common genetic variants influencing gross human brain structure as measured through magnetic resonance imaging. In this review, we contextualize imaging genetic associations as one important link in understanding the causal chain from genetic variant to increased risk for neuropsychiatric disorders. We provide examples in other fields of how identifying genetic variant associations to disease and multiple phenotypes along the causal chain has revealed a mechanistic understanding of disease risk, with implications for how imaging genetics can be similarly applied. We discuss current findings in the imaging genetics research domain, including that common genetic variants can have a slightly larger effect on brain structure than on risk for disorders like schizophrenia, indicating a somewhat simpler genetic architecture. Also, gross brain structure measurements share a genetic basis with some, but not all, neuropsychiatric disorders, invalidating the previously held belief that they are broad endophenotypes, yet pinpointing brain regions likely involved in the pathology of specific disorders. Finally, we suggest that in order to build a more detailed mechanistic understanding of the effects of genetic variants on the brain, future directions in imaging genetics research will require observations of cellular and synaptic structure in specific brain regions beyond the resolution of magnetic resonance imaging. We expect that integrating genetic associations at biological levels from synapse to sulcus will reveal specific causal pathways impacting risk for neuropsychiatric disorders.

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“…So zeigten sich häufiger schwere kognitive Defizite [4,5] und stärkere Einschränkungen der allgemeinen sozialen und Alltagsfunktionsfähigkeit [6]. Diese und weitere Ergebnisse legen auch nahe, dass die Adoleszenz aufgrund des Hirnreifungsprozesses ein besonders vulnerables Alter für die Erstmanifestation sowie für negative Konsequenzen einer Psychose darstellt [1,7,8]. Die Nachteile eines frühen Erkrankungsalters, vor allem hinsichtlich einer langen Dauer der unbehandelten Erkrankung und daraus resultierender höherer Krankheitsschwere bei Beginn einer spezifischen Behandlung, können jedoch zumindest teilweise durch eine systematische Früherkennung und Frühbehandlung ausgeglichen werden [9].…”

Section: Epidemiologie Kernsymptome Und Verlaufunclassified

Früherkennung und Frühintervention bei psychotischen Störungen in der Transitionsphase

Karow

Holtmann²,

Koutsouleris

et al. 2019

Fortschr Neurol Psychiatr

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ZusammenfassungDie Adoleszenz ist aufgrund des Hirnreifungsprozesses und vor allem bei zusätzlichen Belastungsfaktoren ein besonders vulnerables Alter für die Erstmanifestation von Psychosen mit negativen psychosozialen Konsequenzen für die Betroffenen und ihre Angehörigen. Die Nachteile eines frühen Erkrankungsalters können teilweise durch eine hochqualitative Früherkennung und Frühbehandlung unter einer Berücksichtigung transitionsmedizinischer Versorgungsansätze ausgeglichen werden. Für die Förderung einer erfolgreichen Transition heranwachsender PatientInnen mit Psychosen bestehen praxisbezogene Empfehlungen zum Aufbau populationsbezogener, flexibler und nachgehender Früherkennungs- und Behandlungsnetzwerke, in denen MitarbeiterInnen diagnose-, alters- und fachübergreifend settingübergreifend zusammenarbeiten und eine erfolgreiche Transition strukturiert, flächendeckend, patientenorientiert und flexibel ermöglichen.

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Pruning hypothesis comes of age

Cited by 38 publications

References 14 publications

Neuronal NR4A1 and complement coordinate synaptic stripping by microglia in lupus

Neuronal NR4A1 and complement coordinate synaptic stripping by microglia in lupus

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

Früherkennung und Frühintervention bei psychotischen Störungen in der Transitionsphase

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