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Disruption of the Microglial ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis

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Disruption of the Microglial ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis ORIGINAL RESEARCH published: 17 May 2018 doi: 10.3389/fncel.2018.00134 Disruption of the Microglial ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis Jennifer Stefani 1, Olga Tschesnokowa 1†, Marta Parrilla 1,2†, Bernard Robaye 3, Jean-Marie Boeynaems 3, Amparo Acker-Palmer 1,2,4, Herbert Zimmermann 1* and Kristine Gampe 1 1Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt am Main, Germany, 2Max-Planck-Institute for Brain Research, Frankfurt am Main, Germany, 3Institute of Interdisciplinary Research, School of Medicine, Université Libre de Bruxelles, Bruxelles, Belgium, 4Focus Program Translational Neurosciences (FTN), University of Mainz, Mainz, Germany In mammalian species, including humans, the hippocampal dentate gyrus (DG) is a primary region of adult neurogenesis. Aberrant adult hippocampal neurogenesis is associated with neurological pathologies. Understanding the cellular mechanisms controlling adult hippocampal neurogenesis is expected to open new therapeutic strategies for mental disorders. Microglia is intimately associated with neural progenitor cells in the hippocampal DG and has been implicated, under varying experimental conditions, in the control of the proliferation, differentiation and survival of neural precursor cells. But the underlying mechanisms remain poorly defined. Using fluorescent Edited by: in situ hybridization we show that microglia in brain express the ADP-activated Oscar Gonzalez-Perez, P2Y13 receptor under basal conditions and that P2ry13 mRNA is absent from University of Colima, Mexico neurons, astrocytes, and neural progenitor cells. Disrupting P2ry13 decreases structural Reviewed by: Amanda Sierra, complexity of microglia in the hippocampal subgranular zone (SGZ). But it increases Achucarro Basque Center for progenitor cell proliferation and new neuron formation. Our data suggest that P2Y13 Neuroscience, Spain Hui Peng, receptor-activated microglia constitutively attenuate hippocampal neurogenesis. This University of Kentucky, United States identifies a signaling pathway whereby microglia, via a nucleotide-mediated mechanism, *Correspondence: contribute to the homeostatic control of adult hippocampal neurogenesis. Selective Herbert Zimmermann P2Y R antagonists could boost neurogenesis in pathological conditions associated [email protected] 13 with impaired hippocampal neurogenesis. †These authors have contributed equally to this work. Keywords: adult neurogenesis, ADP, ATP, dentate gyrus, hippocampus, microglia, P2Y13 receptor, progenitor cell Received: 16 March 2018 Accepted: 30 April 2018 INTRODUCTION Published: 17 May 2018 Microglia have long been known as major orchestrators of the brain inflammatory response. Citation: Stefani J, Tschesnokowa O, They actively move to sites of damage and engulf and eliminate neural debris. But microglia also Parrilla M, Robaye B, contribute to physiological brain functions. They continuously survey their cellular environment Boeynaems J-M, Acker-Palmer A, and regulate neuronal survival, migration of neurons, axonal growth, pruning of supernumerary Zimmermann H and Gampe K synapses, and functional maturation of developing synapses (Nayak et al., 2014; Sierra et al., 2014). (2018) Disruption of the Microglial The role of microglia in the control of developmental and adult neuron formation has recently ADP Receptor P2Y13 Enhances Adult Hippocampal Neurogenesis. received increasing attention (Gemma and Bachstetter, 2013). Microglia is intimately associated Front. Cell. Neurosci. 12:134. with neural progenitor cells in the adult hippocampal dentate gyrus (DG) and has been implicated doi: 10.3389/fncel.2018.00134 in the control of neurogenesis. But the underlying mechanisms remain poorly defined. Frontiers in Cellular Neuroscience| www.frontiersin.org 1 May 2018 | Volume 12 | Article 134 Stefani et al. Microglial P2Y13R in Hippocampal Neurogenesis In mammalian species, including humans, the hippocampal situation, essentially all P2 receptors are expressed by cultured DG is a primary region of adult neurogenesis (Frisén, microglia (Bianco et al., 2005). Moreover, culturing greatly alters 2016). Hippocampal neurogenesis confers an additional level microglial P2 receptor expression (Crain et al., 2009), suggesting of plasticity to the adult brain and has been implicated that in situ analyses are essential for evaluating the implication in memory consolidation, pattern separation, and mood of P2 receptors in microglial function. Nucleotide receptors regulation but also in regulating ‘‘forgetting’’ (Christian et al., expressed by microglia in situ include the ATP-activated 2014). Moreover, aberrant adult hippocampal neurogenesis P2X7 and P2X4 receptors which are strongly upregulated is associated with neurological pathologies. Understanding under diverse pathological conditions, the Gq-coupled and the molecular mechanisms controlling adult hippocampal UDP-activated P2Y6 receptor (P2Y6R) and three closely related neurogenesis is expected to open new therapeutic strategies for Gi-coupled receptors, the ADP-activated receptors P2Y12 mental disorders such as depression or schizophrenia (Jun et al., (P2Y12R) and P2Y13 (P2Y13R), and the UDP-glucose/UDP- 2012). Multiple evidence suggests that new neuron formation in activated P2Y14 receptor (P2Y14R). The P2Y6R has been the DG is initiated by the activation of astroglia-like type 1 cells implicated in microglial phagocytosis (Koizumi et al., 2007) whose cell bodies are located in the subgranular zone (SGZ), and the P2Y12R in mediating rapid microglial chemotaxis at followed by several intimately apposed transient functional early stages of the response to local CNS injury (Haynes et al., cellular stages, which can be addressed by specific marker 2006). profiles. Type 1 cells give rise to highly proliferating intermediate The more recently characterized P2Y13R(Communi et al., progenitor cells (type 2 cells) enlarging the neurogenic pool. The 2001; Zhang et al., 2002) is expressed in several tissues, including next stage comprises fate specification and the formation of type spleen, bone, liver, pancreas, and heart, or also in peripheral 3 cells (neuroblasts). These exhibit little proliferating activity and leukocytes (Pérez-Sen et al., 2017). P2ry13 KO mice exhibit a give rise to mature excitatory principal neurons that become small increase in bone area but no other major abnormalities. incorporated into the granule cell layer (GCL; Kempermann Body weight, fat mass, and lean body mass are normal. Hepatic et al., 2015). high-density lipoprotein (HDL) cholesterol uptake and biliary Neurogenesis needs to be under strict homeostatic control, cholesterol content and output were found to be decreased. But tightly balancing new neuron formation via proneurogenic their plasma HDL levels and other lipid levels were described as mechanisms and neurogenesis-attenuating mechanisms. These normal or only slightly decreased (Blom et al., 2010; Fabre et al., include the control of cell proliferation, elimination of surplus 2010). The P2Y13R is also expressed by osteoblasts and involved cells, and new neuron formation. A considerable variety of in osteogenesis. Studies on P2ry13 KO mice reveal a decreased external signaling cues, including growth factors, neurotrophic bone turnover associated with a reduction in the number of factors, and neurotransmitters as well as intracellular signaling osteoblasts and osteoclasts at the bone surface (Wang et al., 2012) pathways and epigenetic regulators have been implicated in and an impact of the receptor on the balance of the terminal the control of adult hippocampal neurogenesis. Factors may differentiation of bone marrow progenitors into osteoblasts and be derived from the neurogenic niche including its vasculature adipocytes (Biver et al., 2013). or from axonal inputs (Aimone et al., 2014; Gonçalves et al., Expression of the P2Y13R in cultured neurons (Miras- 2016; Yao et al., 2016). Increasing evidence suggests that Portugal et al., 2016), cultured astroglia (Carrasquero et al., 2009) extracellular nucleotides contribute to the control of both and spinal cord microglia in situ (Kobayashi et al., 2012) has been embryonic and adult neurogenesis (Lecca et al., 2016; Oliveira reported. After peripheral nerve injury the P2Y13R is upregulated et al., 2016). They activate specific receptors representing in spinal cord microglia together with the P2Y6R, the P2Y12R, C C 2C either Na ,K and Ca permeable ion channels (seven P2X and the P2Y14R(Kobayashi et al., 2012) and may be involved receptors) or G protein-coupled receptors (in rodents seven in the induction and maintenance of neuropathic pain (Tatsumi P2Y receptors). Nucleotides function as primary messengers et al., 2015). Otherwise functional roles of the P2Y13R or of in intercellular communication and can stimulate the release the P2Y14R in the central nervous system in situ are unknown. of other extracellular messenger substances. Depending on Importantly, the impact of the P2Y13R may have been overlooked receptor subtype, these include hormones, neurotransmitters, in previous studies targeting the P2Y12R and using ligands that growth factors, a considerable variety of other proteins are now known to antagonize both the P2Y12 and P2Y13R (2- including enzymes, numerous cytokines, lipid mediators, nitric methylthio-AMP and AR-C69931MX). oxide, and reactive oxygen species. Moreover, nucleotides In this study we determined the cellular expression
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