Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior

Zhan, Yang; Paolicelli, Rosa Chiara; Sforazzini, Francesco; Weinhard, Laetitia; Bolasco, Giulia; Pagani, Francesca; Vyssotski, Alexei L.; Bifone, Angelo; Gozzi, Alessandro; Ragozzino, Davide; Gross, Cornelius

doi:10.1038/nn.3641

Cited by 1,030 publications

(977 citation statements)

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“…These synapses are subsequently pruned and the neuronal circuits sculpted/refined by the appearance and proliferation of microglia during key critical periods (Brown & Neher, 2014; Kettenmann et al, 2013; Paolicelli et al, 2011). Evidence for the importance of microglia‐mediated synaptic pruning and refining during development comes from observations that transgenic mice with perturbed microglial function have impaired cognitive function and synaptic plasticity (Rogers et al, 2011), decreased synaptic pruning, and display autistic‐like phenotypes (Zhan et al, 2014). Microglia numbers are elevated during the period of synaptic pruning in development, and following this, microglia numbers then fall to those found in the adult mouse brain (Nikodemova et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony‐stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a “primed” phenotype and studies indicate that this coincides with age‐related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor‐induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation‐related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age‐related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age‐related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age‐induced deficits in long‐term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.

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Section: Discussionmentioning

confidence: 99%

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

et al. 2018

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“…Disrupting the fine regulation between circulating immune cells, macrophages, microglia, and neurons or the imbalance in immune molecules can cause a pro-inflammatory skew and produce changes in neuronal function. 46,47 Several immune-related molecules have been shown to have pleiotropic functions in the brain that can directly influence synaptic function. 48,49 LAT encodes a transmembrane adaptor protein with a role in the development, activation, and maintenance of T cells.…”

Section: Discussionmentioning

confidence: 99%

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Loviglio

Arbogast

Jønch³

et al. 2017

The American Journal of Human Genetics

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Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%-1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb BP2-BP3 CNV is likewise a potent driver of neuropsychiatric, anatomical, and metabolic pathologies. These two CNVs are engaged in complex reciprocal chromatin looping, intimating a functional relationship between genes in these regions that might be relevant to pathomechanism. We assessed the drivers of the distal 16p11.2 duplication by overexpressing each of the nine encompassed genes in zebrafish. Only overexpression of LAT induced a reduction of brain proliferating cells and concomitant microcephaly. Consistently, suppression of the zebrafish ortholog induced an increase of proliferation and macrocephaly. These phenotypes were not unique to zebrafish; Lat knockout mice show brain volumetric changes. Consistent with the hypothesis that LAT dosage is relevant to the CNV pathology, we observed similar effects upon overexpression of CD247 and ZAP70, encoding members of the LAT signalosome. We also evaluated whether LAT was interacting with KCTD13, MVP, and MAPK3, major driver and modifiers of the proximal 16p11.2 600 kb BP4-BP5 syndromes, respectively. Co-injected embryos exhibited an increased microcephaly, suggesting the presence of genetic interaction. Correspondingly, carriers of 1.7 Mb BP1-BP5 rearrangements that encompass both the BP2-BP3 and BP4-BP5 loci showed more severe phenotypes. Taken together, our results suggest that LAT, besides its well-recognized function in T cell development, is a major contributor of the 16p11.2 220 kb BP2-BP3 CNV-associated neurodevelopmental phenotypes.

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“…CX3CL1 is expressed on subsets of neurons in the CNS, particularly within the striatum, hippocampus, and cortical layer II (Kim et al, 2011), although the mechanism regulating this heterogeneous expression is unknown. Disruptions to CX3CR1 can increase neurotoxicity, delay synapse maturation in the hippocampus, and result in social interaction deficits (Cardona et al, 2006;Paolicelli et al, 2011;Zhan et al, 2014). The maintenance and survival of microglia also depends on signaling at colony stimulating factor 1 receptor (CSF1R).…”

Section: Future Research Directions and Clinical Implicationsmentioning

confidence: 99%

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

Lacagnina

Rivera

Bilbo

2016

Neuropsychopharmacol

223

170

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Drugs of abuse cause persistent alterations in synaptic plasticity that may underlie addiction behaviors. Evidence suggests glial cells have an essential and underappreciated role in the development and maintenance of drug abuse by influencing neuronal and synaptic functions in multifaceted ways. Microglia and astrocytes perform critical functions in synapse formation and refinement in the developing brain, and there is growing evidence that disruptions in glial function may be implicated in numerous neurological disorders throughout the lifespan. Linking evidence of function in health and under pathological conditions, this review will outline the glial and neuroimmune mechanisms that may contribute to drug-abuse liability, exploring evidence from opioids, alcohol, and psychostimulants. Drugs of abuse can activate microglia and astrocytes through signaling at innate immune receptors, which in turn influence neuronal function not only through secretion of soluble factors (eg, cytokines and chemokines) but also potentially through direct remodeling of the synapses. In sum, this review will argue that neural-glial interactions represent an important avenue for advancing our understanding of substance abuse disorders.

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Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior

Cited by 1,030 publications

References 60 publications

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

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