Microglia: Architects of the Developing Nervous System

Frost, Jeffrey L.; Schafer, Dorothy P.

doi:10.1016/j.tcb.2016.02.006

Cited by 285 publications

(225 citation statements)

References 111 publications

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“…This has been noted in other developing CNS structures, such as the cerebral cortex [39]. Why microglia in many regions of the developing brain display the activated phenotype has not yet been determined, but may be related to the developmental functions attributed to microglial cells, including regulation of cell number and spatial patterning of CNS cells, myelination, and formation and refinement of neuronal circuits [48]. …”

Section: Discussionmentioning

confidence: 96%

“…We show for the first time that microglia begin to colonize the rat pineal neuroepithelium at the earliest stage of gland formation before pinealocyte differentiation has commenced (Fig 5A 1 –5A 5 ). This timing of microglial colonization is a common feature in the developing brain [48]. Microglia appear to populate the pineal primordium from the meninges and also from the choroid plexus of the third ventricle.…”

Section: Discussionmentioning

confidence: 99%

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Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator

2016

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The adult pineal gland is composed of pinealocytes, astrocytes, microglia, and other interstitial cells that have been described in detail. However, factors that contribute to pineal development have not been fully elucidated, nor have pineal cell lineages been well characterized. We applied systematic double, triple and quadruple labeling of cell-specific markers on prenatal, postnatal and mature rat pineal gland tissue combined with confocal microscopy to provide a comprehensive view of the cellular dynamics and cell lineages that contribute to pineal gland development. The pineal gland begins as an evagination of neuroepithelium in the roof of the third ventricle. The pineal primordium initially consists of radially aligned Pax6+ precursor cells that express vimentin and divide at the ventricular lumen. After the tubular neuroepithelium fuses, the distribution of Pax6+ cells transitions to include rosette-like structures and later, dispersed cells. In the developing gland all dividing cells express Pax6, indicating that Pax6+ precursor cells generate pinealocytes and some interstitial cells. The density of Pax6+ cells decreases across pineal development as a result of cellular differentiation and microglial phagocytosis, but Pax6+ cells remain in the adult gland as a distinct population. Microglial colonization begins after pineal recess formation. Microglial phagocytosis of Pax6+ cells is not common at early stages but increases as microglia colonize the gland. In the postnatal gland microglia affiliate with Tuj1+ nerve fibers, IB4+ blood vessels, and Pax6+ cells. We demonstrate that microglia engulf Pax6+ cells, nerve fibers, and blood vessel-related elements, but not pinealocytes. We conclude that microglia play a role in pineal gland formation and homeostasis by regulating the precursor cell population, remodeling blood vessels and pruning sympathetic nerve fibers.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Cellular Basis of Pineal Gland Development: Emerging Role of Microglia as Phenotype Regulator

2016

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“…Microglia are critical to the development of the embryonic and postnatal brain (Frost and Schafer 2016), yet data connecting early microglia function to behavioral maturation is currently lacking. One such study, published during the preparation of this manuscript, used a similar approach to address this issue (Nelson and Lenz, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that microglia are most critical for establishing brain architecture and circuitry necessary for normal behavior (Frost and Schafer, 2016), and little research has investigated the influence of microglia on the organization of brain and behavior during early periods of development.…”

Section: Introductionmentioning

confidence: 99%

Temporary Depletion of Microglia during the Early Postnatal Period Induces Lasting Sex-Dependent and Sex-Independent Effects on Behavior in Rats

VanRyzin

Pérez-Pouchoulén

et al. 2016

eNeuro

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Microglia are the primary immune cells of the brain and function in multiple ways to facilitate proper brain development. However, our current understanding of how these cells influence the later expression of normal behaviors is lacking. Using the laboratory rat, we administered liposomal clodronate centrally to selectively deplete microglia in the developing postnatal brain. We then assessed a range of developmental, juvenile, and adult behaviors. Liposomal clodronate treatment on postnatal days 0, 2, and 4 depleted microglia with recovery by about 10 days of age and induced a hyperlocomotive phenotype, observable in the second postnatal week. Temporary microglia depletion also increased juvenile locomotion in the open field test and decreased anxiety-like behaviors in the open field and elevated plus maze. These same rats displayed reductions in predator odor–induced avoidance behavior, but increased their risk assessment behaviors compared with vehicle-treated controls. In adulthood, postnatal microglia depletion resulted in significant deficits in male-specific sex behaviors. Using factor analysis, we identified two underlying traits—behavioral disinhibition and locomotion—as being significantly altered by postnatal microglia depletion. These findings further implicate microglia as being critically important to the development of juvenile and adult behavior.

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“…Moreover, microglia are involved in synaptic pruning and may release neurotrophic factors, including insulin-like growth factor 1 and brain-derived neurotrophic factor, demonstrating that these cells are architects in the developing brain [16][17][18][19][20]. Based on studies in mice, synaptic pruning might be achieved via a complement-dependent mechanism because disruption of complement receptor 3 on microglia led to deficits in synaptic engulfment [21,22].…”

Section: Trem2: Presenting Microglia Front and Center In Admentioning

confidence: 99%