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.

Download full-text


Available from: Amanda Sierra,
  • Source
    • "n, number of spines. early critical period (1–4 days after cell birth) and a secondary, late critical period (1–3 weeks after cell birth) (Sierra et al., 2010). At the early stage the majority of adult-born cells undergo apoptosis as they develop from late proliferating amplifying neuroprogenitors to early neuroblasts. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The survival of adult-born dentate gyrus granule cells critically depends on their synaptic integration into the existing neuronal network. Excitatory inputs are thought to increase the survival rate of adult born neurons. Therefore, we tested whether enhancing the stability of newly formed excitatory synapses by overexpressing the synaptic cell adhesion molecule SynCAM 1 improves the survival of adult-born neurons. Here we show that overexpression of SynCAM 1 improves survival of adult-born neurons, but has no effect on the proliferation rate of precursor cells. As expected, overexpression of SynCAM 1 increases the synapse density in adult-born granule neurons. While adult-born granule neurons have very few functional synapses 15 days after birth, we found that at this age adult-born neurons in SynCAM 1 overexpressing mice exhibited around three times more excitatory synapses, which were stronger than synapses of adult-born neurons of control littermates. In summary, our data indicate that additional SynCAM 1 accelerates synapse maturation, which improves the stability of newly formed synapses and in turn increases the likelihood of survival of adult-born neurons. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    Hippocampus 09/2015; DOI:10.1002/hipo.22524 · 4.16 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
Show more