Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia

Park, Ho‐Jin; Noh, Haneul; Shao, Zhicheng; Ni, Peiyan; Qin, Yiren; Liu, Dongxin; Beaudreault, Cameron; Park, Joy S.; Abani, Chiderah P; Park, James M.; Le, Derek T; Gonzalez, Sasha Z; Guan, Youxin; Cohen, Bruce M.; McPhie, Donna L.; Coyle, Joseph T.; Lanz, Thomas A.; Xi, Hualin Simon; Yin, Changhong; Huang, Weihua; Kim, Hae-Young; Chung, Sangmi

doi:10.1038/s41593-020-00724-1

Cited by 57 publications

(56 citation statements)

References 55 publications

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“…Early aberrant MG activation in cases of PBI may interfere with these cellular processes [ 141 ]. A recent interesting study investigated the specific effects on MG on interneurons derived from iPSC [ 149 ]. This novel study identified that inflammatory-activated MG induced profound changes in the interneurons including compromising energy-dependent neuronal processes such as arborization, synapse formation and synaptic GABA release.…”

Section: Microglia and Other Cellular Brain Partnersmentioning

confidence: 99%

Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries

et al. 2021

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Perinatal brain injuries, including encephalopathy related to fetal growth restriction, encephalopathy of prematurity, neonatal encephalopathy of the term neonate, and neonatal stroke, are a major cause of neurodevelopmental disorders. They trigger cellular and molecular cascades that lead in many cases to permanent motor, cognitive, and/or behavioral deficits. Damage includes neuronal degeneration, selective loss of subclasses of interneurons, blocked maturation of oligodendrocyte progenitor cells leading to dysmyelination, axonopathy and very likely synaptopathy, leading to impaired connectivity. The nature and severity of changes vary according to the type and severity of insult and maturation stage of the brain. Microglial activation has been demonstrated almost ubiquitously in perinatal brain injuries and these responses are key cell orchestrators of brain pathology but also attempts at repair. These divergent roles are facilitated by a diverse suite of transcriptional profiles and through a complex dialogue with other brain cell types. Adding to the complexity of understanding microglia and how to modulate them to protect the brain is that these cells have their own developmental stages, enabling them to be key participants in brain building. Of note, not only do microglia help build the brain and respond to brain injury, but they are a key cell in the transduction of systemic inflammation into neuroinflammation. Systemic inflammatory exposure is a key risk factor for poor neurodevelopmental outcomes in preterm born infants. Based on these observations, microglia appear as a key cell target for neuroprotection in perinatal brain injuries. Numerous strategies have been developed experimentally to modulate microglia and attenuate brain injury based on these strong supporting data and we will summarize these.

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Section: Microglia and Other Cellular Brain Partnersmentioning

confidence: 99%

Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries

et al. 2021

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“…The authors indeed found increased synapse elimination in cells from patients suffering from SCZ and also implicated minocycline, an antimicrobial chemotherapeutic drug, in the reduction of synapse elimination through microglia ( Sellgren et al, 2019 ). This association was further corroborated by showing persistent changes through microglia in iPSC-derived interneurons of patients suffering from SCZ ( Park et al, 2020 ). Cortical interneurons generated from iPSCs of patients with SCZ also exhibit aberrant arborization and synaptic density, a phenotype that seems to be corrected when applying an inhibitor of protein kinase C ( Shao et al, 2019 ).…”

Section: Neuronal Models For Disorders Of the Brainmentioning

confidence: 70%

Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders

Unterholzner

Millischer

Wotawa

et al. 2021

International Journal of Neuropsychopharmacology

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The improvement of experimental models for disorders requires a constant approximation towards the dysregulated tissue. In psychiatry, where an impairment of neuronal structure and function is assumed to play a major role in disease mechanisms and symptom development, this approximation is an ongoing process implicating various fields. These include genetic, animal, and post-mortem studies. To test hypotheses generated through these studies in vitro models using non-neuronal cells such as fibroblasts and lymphocytes have been developed. For brain network disorders, cells with neuronal signatures would, however, represent a more adequate tissue. Considering the limited accessibility of brain tissue, research has thus turned towards neurons generated from induced pluripotent stem cells, as well as directly induced neurons, cerebral organoids, and olfactory neuroepithelium. Regarding the increasing importance and amount of research using these neuronal cells, this review aims to provide an overview of all these models, to make sense of the current literature. The development of each model system and its use as models for the various psychiatric disorder categories will be laid out. Also, advantages and limitations of each model will be discussed including a reflection on implications and future perspectives.

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“… 12 , 13 Furthermore, our findings are supported by previous studies showing that immune activation of stem cell-derived neurons from healthy individuals result in downregulation of schizophrenia genes 22 and co-culture of stem cell-derived neurons with immune activated microglia give rise to lasting changes in schizophrenia patient interneurons. 23 …”

Section: Discussionmentioning

confidence: 99%

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

Handunnetthi

Hamley

Knight

2021

Brain Communications

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Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Maternal immune activation by infections during pregnancy is hypothesized to be a key environmental risk factor. However, little is known about how maternal immune activation contributes to schizophrenia pathogenesis. In this study, we investigated if maternal immune activation influences the expression of genes associated with schizophrenia in foetal mouse brains. We found that two sets of schizophrenia genes were downregulated more than expected by chance in the foetal mouse brain following maternal immune activation, namely those genes associated with schizophrenia through genome-wide association study (fold change = 1.93, false discovery rate = 4 × 10−4) and downregulated genes in adult schizophrenia brains (fold change = 1.51, false discovery rate = 4 × 10−10). We found that these genes mapped to key biological processes, such as neuronal cell adhesion. We also identified cortical excitatory neurons and inhibitory interneurons as the most vulnerable cell types to the deleterious effects of this interaction. Subsequently, we used gene expression information from herpes simplex virus 1 infection of neuronal precursor cells as orthogonal evidence to support our findings and to demonstrate that schizophrenia-associated cell adhesion genes, PCDHA2, PCDHA3 and PCDHA5, were downregulated following herpes simplex virus 1 infection. Collectively, our results provide novel evidence for a link between genetic and environmental risk factors in schizophrenia pathogenesis. These findings carry important implications for early preventative strategies in schizophrenia.

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Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia

Cited by 57 publications

References 55 publications

Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries

Microglia-Mediated Neurodegeneration in Perinatal Brain Injuries

Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain

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