Microglia Shape Adult Hippocampal Neurogenesis through Apoptosis-Coupled Phagocytosis

Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell stem cell (Impact Factor: 22.27). 10/2010; 7(4):483-95. DOI: 10.1016/j.stem.2010.08.014
Source: PubMed


In the adult hippocampus, neuroprogenitor cells in the subgranular zone (SGZ) of the dentate gyrus give rise to newborn neuroblasts. However, only a small subset of these cells integrates into the hippocampal circuitry as mature neurons at the end of a 4 week period. Here, we show that the majority of the newborn cells undergo death by apoptosis in the first 1 to 4 days of their life, during the transition from amplifying neuroprogenitors to neuroblasts. These apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche. Phagocytosis by the microglia is efficient and undeterred by increased age or inflammatory challenge. Our results suggest that the main critical period of newborn cell survival occurs within a few days of birth and reveal a new role for microglia in maintaining the homeostasis of the baseline neurogenic cascade.

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Available from: Amanda Sierra, Sep 30, 2015
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    • "Microglia, the innate immune cells of the brain, exhibit a dual role in adult neurogenesis. Under physiological conditions, microglia phagocytose apoptotic neuronal progenitor cells and promote neuronal differentiation via trophic factors [8] [9]. Conversely, following seizures, both detrimental and a supportive role for activated microglia have been described [5] [10]. "
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    ABSTRACT: Adult hippocampal neurogenesis is modulated by physiological and pathological stimuli, including seizures and inflammation. Here, we describe stable interactions between microglia and newborn neurons using two-photon and confocal microscopy. On 3 weeks-old neurons, these interactions exhibit preferences for distal dendrites under physiological conditions. Conversely, after status epilepticus, ramified microglia, in particular, interact more with the proximal dendrites of new neurons. No such differences were found on 6 weeks-old neurons. Our study demonstrates regional and temporal specificity of the interactions between newborn neurons and microglia during a critical period for homeostasis and synaptic integration.
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    • "While regulation of stem cell behavior due to systemic factors has been little studied until now, recent work from our lab indicates that they may in fact be of paramount importance, particularly after injury (Lin et al., 2015) (see discussion of cues below). Also present in both forebrain niches are microglial cells which have become a focus of great interest in recent years (Ekdahl et al., 2009; Molina-Holgado and Molina-Holgado, 2010; Russo et al., 2011; Sierra et al., 2010; Whitney et al., 2009). Although the exact nature of their interaction with stem cells in the niche remains enigmatic, it is now believed that microglia are important in regulating neurogenesis in the healthy and in the injured/diseased brain. "
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    ABSTRACT: Neural stem cells (NSCs) critical for the continued production of new neurons and glia are sequestered in distinct areas of the brain called stem cell niches. Until recently, only two forebrain sites, the subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampus, have been recognized adult stem cell niches (Alvarez-Buylla and Lim, 2004; Doetsch et al., 1999a, 1999b; Doetsch, 2003a, 2003b; Lie et al., 2004; Ming and Song, 2005). Nonetheless, the last decade has been witness to a growing literature suggesting that in fact the adult brain contains stem cell niches along the entire extent of the ventricular system. These niches are capable of widespread neurogenesis and gliogenesis, particularly after injury (Barnabé-Heider et al., 2010; Carlén et al., 2009; Decimo et al., 2012; Lin et al., 2015; Lindvall and Kokaia, 2008; Robins et al., 2013) or other inductive stimuli (Bennett et al., 2009; Cunningham et al., 2012; Decimo et al., 2011; Kokoeva et al., 2007, 2005; Lee et al., 2012; Migaud et al., 2010; Pencea et al., 2001b; Sanin et al., 2013; Suh et al., 2007; Sundholm-Peters et al., 2004; Xu et al., 2005; Zhang et al., 2007). This review focuses on the role of these novel and classic brain niches in maintaining adult neurogenesis and gliogenesis in response to normal physiological and injury-related pathological cues. Copyright © 2015. Published by Elsevier B.V.
    Brain research 04/2015; 219. DOI:10.1016/j.brainres.2015.04.029 · 2.84 Impact Factor
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    • " neurogenic cascade , where newborn neurons undergo apoptosis throughout adulthood , and a combination of TEM , confocal microscopy , and unbiased stereology methods of quantification it was shown that apoptosis and microglial phago - cytosis are tightly coupled , and that phagocytosis of apoptotic cells is fully executed under 90 min on average ( Sierra et al . , 2010 ) . Two - photon in vivo imaging and TEM also revealed that microglia make use of their potential as phagocytes in the healthy brain to eliminate axon terminals , dendritic spines , and pos - sibly entire excitatory synapses during post - natal development , adulthood and aging . In particular , microglial processes harbor - ing phagocy"
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    ABSTRACT: Under the guidance of Ramón y Cajal, a plethora of students flourished and began to apply his silver impregnation methods to study brain cells other than neurons: the neuroglia. In the first decades of the XXth century, Nicolás Achúcarro was one of the first researchers to visualize the brain cells with phagocytic capacity that we know today as microglia. Later, his pupil Pío del Río-Hortega developed modifications of Achúcarro´s methods and was able to specifically observe the fine morphological intricacies of microglia. These findings contradicted Cajal´s own views on cells that he thought belonged to the same class as oligodendroglia (the so called “third element” of the nervous system), leading to a long-standing discussion. It was only in 1924 that Río-Hortega´s observations prevailed worldwide, thus recognizing microglia as a unique cell type. This late landing in the Neuroscience arena still has repercussions in the XXIst century, as microglia remain one of the least understood cell populations of the healthy brain. For decades, microglia in normal, physiological conditions in the adult brain were considered to be merely “resting”, and their contribution as “activated” cells to the neuroinflammatory response in pathological conditions mostly detrimental. It was not until microglia were imaged in real time in the intact brain using two-photon in vivo imaging that the extreme motility of their fine processes was revealed. These findings led to a conceptual revolution in the field: “resting” microglia are constantly surveying the brain parenchyma in normal physiological conditions. Today, following Cajal’s school of thought, structural and functional investigations of microglial morphology, dynamics, and relationships with neurons and other glial cells are experiencing a renaissance and we stand at the brink of discovering new roles for these unique immune cells in the healthy brain, an essential step to understand their causal relationship to diseases.
    Frontiers in Neuroanatomy 03/2015; 9(45). DOI:10.3389/fnana.2015.00045 · 3.54 Impact Factor
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