Microglial Phagocytosis of Newborn Cells Is Induced by Endocannabinoids and Sculpts Sex Differences in Juvenile Rat Social Play

VanRyzin, Jonathan W.; Marquardt, Ashley E.; Argue, Kathryn J.; Vecchiarelli, Haley A.; Ashton, Sydney E.; Arambula, Sheryl E.; Hill, Matthew N.; McCarthy, Margaret M.

doi:10.1016/j.neuron.2019.02.006

Cited by 217 publications

(171 citation statements)

References 62 publications

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“…Previous studies from our lab found no sex differences in cell death during the time points analyzed here (Ahern et al , ; Mosley et al , ; Castillo‐Ruiz et al , ; ). We, and others, also have not found sex differences in microglial number or morphology in newborn mice (Strahan et al , ; Hanamsagar et al , ; Castillo‐Ruiz et al , ), although such sex differences have been reported in rats (Schwarz et al , ; VanRyzin et al ., ) and adult mice (Hanamsagar et al , ; Guneykaya et al , ; Villa et al , ). Two‐tailed independent t‐tests were used to compare saline and clodronate liposome groups for density of Iba1+ and AC3+ cells.…”

Section: Methodsmentioning

confidence: 99%

Microglial Depletion Causes Region‐Specific Changes to Developmental Neuronal Cell Death in the Mouse Brain

Jacobs

Castillo‐Ruiz

Cisternas

et al. 2019

Developmental Neurobiology

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Developmental neuronal cell death has been characterized as a cell autonomous “suicide” program, but recent findings suggest that microglia play an active role in determining the survival of developing neurons. Results have been contradictory, however, with some studies concluding that microglia promote cell death, while others report that microglia are neuroprotective. Here, we depleted microglia throughout the newborn mouse brain using intracerebroventricular injections of clodronate liposomes, and examined effects on naturally occurring cell death across multiple brain areas. Microglial density varied significantly by brain region, and clodronate liposome treatment at birth reduced the number of microglia in all regions examined. The effect of microglia reduction on cell death, however, varied by region: the number of dying cells was reduced in the medial septum and medial amygdala in clodronate treated animals, but was increased in the oriens layer of the hippocampus, and unchanged in several other brain regions. In most brain regions, the average size of microglia was greater in microglia‐depleted than in control animals, suggesting that the remaining microglia compensate to some extent for a reduction in microglial number. The hippocampal oriens was exceptional in this regard, in that microglial size was reduced following treatment with clodronate. Microglia produce cytokines which mediate many of their effects, and we found higher expression of inflammatory cytokines in the hippocampus than in the septum, independent of clodronate treatment. Thus, microglial depletion has opposite effects on cell death in different brain regions of the newborn brain, which may be related to regional heterogeneity in microglia.

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Section: Methodsmentioning

confidence: 99%

Microglial Depletion Causes Region‐Specific Changes to Developmental Neuronal Cell Death in the Mouse Brain

Jacobs

Castillo‐Ruiz

Cisternas

et al. 2019

Developmental Neurobiology

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“…For example, absence of homeobox protein Hox‐B8 (Hoxb8) or progranulin in microglia leads to obsessive–compulsive disorder (OCD)‐like symptoms in rodents, such as excessive grooming , while absence of Cx3cr1 leads to ASD‐like symptoms . A recent study also observed a sex‐specific role for microglial phagocytosis in male social play , setting the stage for further study of molecular mechanisms by which microglia cause psychiatric symptoms.…”

Section: Tissue‐resident Immunity Of the Brain: Cellular Playersmentioning

confidence: 99%

The immune system and psychiatric disease: a basic science perspective

Bennett

Molofsky

2019

Clinical and Experimental Immunology

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Summary Mental illness exerts a major burden on human health, yet evidence‐based treatments are rudimentary due to a limited understanding of the underlying pathologies. Clinical studies point to roles for the immune system in psychiatric diseases, while basic science has revealed that the brain has an active and multi‐cellular resident immune system that interacts with peripheral immunity and impacts behavior. In this perspective, we highlight evidence of immune involvement in human psychiatric disease and review data from animal models that link immune signaling to neuronal function and behavior. We propose a conceptual framework for linking advances in basic neuroimmunology to their potential relevance for psychiatric diseases, based on the subtypes of immune responses defined in peripheral tissues. Our goal is to identify novel areas of focus for future basic and translational studies that may reveal the potential of the immune system for diagnosing and treating mental illnesses

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“…Microglia function and phenotype differ by brain region across time and are largely determined by their local environment (Table ; Ayata et al, ; Böttcher et al, ; De Biase et al, ; Doorn et al, ; Grabert et al, ; Masuda et al, ; O'Koren et al, ; Stowell et al, ). During early development, microglia may promote neural proliferation and cell survival by secreting pro‐proliferative cytokines (Antony, Paquin, Nutt, Kaplan, & Miller, ; Arnó et al, ; Morgan, Taylor, & Pocock, ; Shigemoto‐Mogami et al, ; Ueno et al, ), while later they may prune superfluous cells by inducing apoptosis and targeted phagocytosis (Ashwell, ; Cunningham et al, ; Ferrer, Bernet, Soriano, del Rio, & Fonseca, ; Marín‐Teva et al, ; Sierra et al, ; VanRyzin et al, ; Wakselman et al, ). Similarly, microglia facilitate axonal outgrowth and ensure appropriate synaptic connectivity by both promoting and pruning excess synapses (Ji et al, ; Lenz et al, ; Lim et al, ; Miyamoto et al, ; Pont‐Lezica et al, ; Schafer et al, ; Squarzoni et al, ; Tremblay, Lowery, & Majewska, ).…”

Section: Microglia Shape Sex‐dependent and Sex‐independent Brain Devementioning

confidence: 99%

“…The majority of developmental processes that require microglia are also sexually differentiated endpoints, including cell proliferation, cell death and survival, and synaptic pruning and synaptogenesis (Table ). In the rat, microglia themselves are also sexually dimorphic, as sex differences in microglia number, morphology, and function in the developing brain have been reported across many brain regions (Lenz et al, ; Schwarz, Sholar, & Bilbo, ; VanRyzin et al, ). These parallel findings indicate microglia are both targets and drivers of sexual differentiation (VanRyzin, Pickett, & McCarthy, ).…”

Section: Microglia Shape Sex‐dependent and Sex‐independent Brain Devementioning

confidence: 99%

“…At the most fundamental level, the main difference between male and female microglia is their chromosome complement (XX for females, XY for males), and the implications for how this may impact microglia function are significant (reviewed in Bordt et al 2019 in this issue). However, many microglia sex differences are only observable shortly after the prenatal androgen surge and can be modulated by exogenous hormone exposure, implicating gonadal hormones as central to microglia diversity (Lenz et al, ; Schwarz et al, ; VanRyzin et al, ).…”

Section: What Makes a Male Or Female Microglia?mentioning

confidence: 99%

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Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

VanRyzin

Marquardt

Pickett

et al. 2019

Glia

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Microglia, the innate immune cells of the brain, have recently been removed from the position of mere sentinels and promoted to the role of active sculptors of developing circuits and cells. Alongside their functions in normal brain development, microglia coordinate sexual differentiation of the brain, a set of processes which vary by region and endpoint like that of microglia function itself. In this review, we highlight the ways microglia are both targets and drivers of brain sexual differentiation. We examine the factors that may drive sex differences in microglia, with a special focus on how changing microenvironments in the developing brain dictate microglia phenotypes and discuss how their diverse functions sculpt lasting sex‐specific changes in the brain. Finally, we consider how sex‐specific early life environments contribute to epigenetic programming and lasting sex differences in microglia identity.

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Microglial Phagocytosis of Newborn Cells Is Induced by Endocannabinoids and Sculpts Sex Differences in Juvenile Rat Social Play

Cited by 217 publications

References 62 publications

Microglial Depletion Causes Region‐Specific Changes to Developmental Neuronal Cell Death in the Mouse Brain

Microglial Depletion Causes Region‐Specific Changes to Developmental Neuronal Cell Death in the Mouse Brain

The immune system and psychiatric disease: a basic science perspective

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

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