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Microglia-Associated Granule Cell Death in the Normal Adult Dentate Gyrus

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Microglia-Associated Granule Cell Death in the Normal Adult Dentate Gyrus View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central Brain Struct Funct (2009) 214:25–35 DOI 10.1007/s00429-009-0231-7 ORIGINAL ARTICLE Microglia-associated granule cell death in the normal adult dentate gyrus Charles E. Ribak • Lee A. Shapiro • Zachary D. Perez • Igor Spigelman Received: 6 August 2009 / Accepted: 11 November 2009 / Published online: 21 November 2009 Ó The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Microglial cells are constantly monitoring the of neuronal edema. The data also show that following this central nervous system for sick or dying cells and patho- localized disintegration of the granule cell’s plasma gens. Previous studies showed that the microglial cells in membrane, the Iba1-labeled microglial cell body is found the dentate gyrus have a heterogeneous morphology with within the electron-lucent perikaryal cytoplasm of the multipolar cells in the hilus and fusiform cells apposed to granule cell, where it is adjacent to the granule cell’s the granule cell layer both at the hilar and at the molecular nucleus which is deformed. We propose that granule cells layer borders. Although previous studies showed that the are dying by a novel microglia-associated mechanism that microglia in the dentate gyrus were not activated, the data involves lysis of their plasma membranes followed by in the present study show dying granule cells apposed by neuronal edema and nuclear phagocytosis. Based on the Iba1-immunolabeled microglial cell bodies and their pro- morphological evidence, this type of cell death differs from cesses both at hilar and at molecular layer borders of the either apoptosis or necrosis. granule cell layer. Initially, these Iba1-labeled microglial cells surround individual, intact granule cell bodies. When Keywords Neurodegeneration Á Neuronal edema Á small openings in the plasma membrane of granule cells Neurogenesis Á Hippocampus Á Membrane lysis are observed, microglial cells are apposed to these open- ings. When larger openings in the plasma membrane occur at this site of apposition, the granule cells display watery Introduction perikaryal cytoplasm, watery nucleoplasm and damaged organelles. Such morphological features are characteristic Microglial cells constitute the macrophage population in the normal adult brain and serve as the primary immune com- ponent in the central nervous system (CNS). These cells are C. E. Ribak and L. A. Shapiro contributed equally to this paper. constantly monitoring the CNS for sick or dying cells, pathogens, and other abnormalities that may require a neuro- C. E. Ribak (&) Á Z. D. Perez immune response (Gehrmann et al. 1995; Nimmerjahn et al. Department of Anatomy and Neurobiology, School of Medicine, 2005; Davalos et al. 2005). When microglial cells encounter University of California at Irvine, Irvine, CA 92697-1275, USA e-mail: [email protected] compromised cells, they may act as antigen presenting cells and they can also remove sick or dying cells through the L. A. Shapiro process of phagocytosis (Thanos et al. 1994; Hirt et al. Department of Surgery and Neurosurgery, 2000). The distribution of microglial cells has been descri- Texas A&M Health Science Center College of Medicine, Scott & White Hospital, Central Texas Veterans Health bed in the adult dentate gyrus using immunocytochemical Care System, Temple, TX 76504, USA methods for markers, such as Mac-1 and ionized calcium binding adaptor molecule 1 (Iba1) (Wirenfeldt et al. 2003; I. Spigelman Jinno et al. 2007; Shapiro et al. 2009). Briefly, they are Division of Oral Biology and Medicine, UCLA School of Dentistry, randomly arranged in the hilus and molecular layer and Los Angeles, CA 90095-1668, USA concentrated on the hilar and molecular layer borders of the 123 26 Brain Struct Funct (2009) 214:25–35 granule cell layer, where they frequently display a fusiform microglia in a ‘‘resting’’ state based upon their morphology, morphology instead of a multipolar shape (Shapiro et al. surface expression of activity markers, and the expression 2009). In the hilus, Iba1-labeled cell bodies appear adjacent level of genes associated with neurogenesis (Olah et al. to capillaries and neuronal somata as well as within the 2009). Therefore, it is plausible to hypothesize that an as yet neuropil (Shapiro et al. 2009). discovered mechanism is present to remove mature granule An unresolved issue in adult brain neurogenesis is that cells to accommodate the structural and functional inte- the birth of relatively large numbers of new neurons in the gration of newborn granule cells (van Praag et al. 2002; hippocampal dentate gyrus does not match the small Kempermann et al. 2003; Zhao et al. 2006; Toni et al. 2007, number of detected dying neurons. Previous studies of 2008; Shapiro et al. 2007) without an enlargement of the granule cell death have demonstrated only small numbers granule cell layer. of dying apoptotic cells, and they were exclusively located The lack of data on the death of mature granule cells in on the hilar border of the granule cell layer, where neural the adult dentate gyrus raises several important issues; (1) progenitors reside (Biebl et al. 2000; Ciaroni et al. 2002; How do they die? (2) Why has their death not been pre- Amrein et al. 2004; Kuhn et al. 2005; Ben Abdallah et al. viously observed? (3) Could a novel mechanism be 2007). These studies can only account for a small degree of responsible for the death and/or removal of mature granule the granule cell death when compared to the data from cells that offsets the functional neurogenesis occurring in several studies of adult neurogenesis that have shown the dentate gyrus? The data in the present study provide 25–77% of newborn neurons surviving (Kempermann et al. evidence for a novel mechanism of dentate granule cell 1997) from as many as 9,000 cells a day being produced death associated with microglial cells. The granule cells (Cameron and McKay 2001). Although the exact number appear to be dying by a process termed ‘‘microglia-asso- of surviving newborn granule cells appears to depend on ciated granule cell death’’ that is characterized by openings numerous factors, such as age, activity level, and the in the plasma membrane of granule cells, followed by environment, functional integration of these newborn neuronal edema and ending with the phagocytosis of the granule cells has been clearly demonstrated (van Praag granule cell’s nucleus and damaged organelles. Also, there et al. 2002; Toni et al. 2007, 2008; Shapiro et al. 2007). are no reactive astrocytes adjacent to the pairs of microglial Therefore, mature granule cells must be dying to provide cell and granule cell bodies. This type of neuronal death space for the newborn neurons to develop and grow their does not fall under the classical criteria of either apoptosis processes. If they were not dying at a rate roughly equal to or necrosis. that of surviving newborn neurons, being produced, the size of the dentate gyrus would continually increase and occupy most of the calvarium. Methods Mature granule cells are mainly located in the middle and outer thirds of the granule cell layer while newborn Animals neurons migrate from the subgranular zone into the inner third of this layer (Christie and Cameron 2006; Overstreet- Young, adult male Sprague–Dawley rats (N = 5) were Wadiche and Westbrook 2006; Laplagne et al. 2007). used for this study. All protocols and experiments were Despite the fact that numerous studies used several markers carried out in accordance with the Institutional Animal for degenerating or dying neurons, no studies have descri- Care and Use Committee at the University of California, bed any pathology occurring for granule cells in normal Irvine. The rats were deeply anesthetized with euthasol and adult brains that are located in the middle or outer portion of transcardial perfusions were carried out using 50–100 ml the granule cell layer, regions where mainly mature granule of 0.9% sterile saline, followed by 200–250 ml of 4.0% cells reside. For example, evidence of neuronal death in this paraformaldehyde. The brains were allowed to post-fix in region of the normal dentate gyrus has eluded recognition in the skull for 24 h, after which they were dissected out and studies that used techniques, such as Fluoro-Jade labeling placed in 4.0% paraformaldehyde for 24 h. The brains (Schmued and Hopkins, 2000), TUNEL staining (Ciaroni were then transferred to phosphate-buffered saline (PBS) et al. 2002; Kuhn et al. 2005), and immunocytochemistry and 50 lm sections were cut using a vibratome. for markers, such as Caspase-3 and BAX (de Bilbao et al. 1999). Furthermore, the microglia in the dentate gyrus do Iba1 immunocytochemistry not generally appear ‘‘activated’’, nor do they appear phagocytic in normal adult animals (Jinno et al. 2007; Sections used for immunocytochemistry were incubated in Shapiro et al. 2008). In fact, exercising mice with their 0.5% H2O2 for 30 min, followed by 60 min in 1% H2O2, concomitant elevated levels of neurogenesis and survival of and then again for 30 min in 0.5% H2O2. Sections were newborn neurons in the dentate gyrus also showed then rinsed with PBS and incubated free-floating in Iba1 123 Brain Struct Funct (2009) 214:25–35 27 antibody (1:1000, Wako, Osaka, Japan), with 3% normal sections from the middle third of the hippocampal slices goat serum, 0.05% Triton-X in PBS, for 24 h rotating at were included in the double-labeling analysis with Iba1 to room temperature (RT). The tissue was then rinsed 3 times decrease the likelihood of including those granule cells for 5 min in PBS and incubated for 1 h in biotinylated anti- which may have been mechanically compromised near the rabbit IgG (1:200, Vector Labs, Burlingame, CA, USA), slice surface during the preparation of the slices.
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