Complement 3 signaling is necessary for the developmental refinement of olfactory bulb circuitry

The olfactory system depends upon organizational maps that are developmentally refined and maintained, however the cellular and molecular mechanisms that underlie these processes are unknown. Studies have shown that microglia and complement molecules are important for the developmental refinement of circuitry within the visual system, thus we asked whether they played a similar role in the olfactory system through the formation of the olfactory bulb (OB) maps, the glomerular and intrabulbar maps. Our findings revealed that microglia in mature animals engulf olfactory sensory neuron (OSN) axons and the synaptic terminals of tufted cells in the glomerular and intrabulbar maps respectively, suggesting microglia could anatomically shape the mature OB circuitry. To determine the mechanisms underlying this axonal pruning activity we used complement 3 (C3) and complement receptor 3 (CR3) knockout mice to investigate if C3 signaling was necessary for precise OB map development. Our results demonstrate that glomerular and intrabulbar map disorganization as typically present in early postnatal mice persists into adulthood when C3 signaling is disrupted. These data clearly establish the C3/CR3 pathway as necessary for the proper developmental refinement of both olfactory maps. We further present the olfactory system as a unique platform to study the role of glia in the development and adult refinement of regenerating circuits.

[1]  A. Anderson,et al.  Complement Protein C3 Suppresses Axon Growth and Promotes Neuron Loss , 2017, Scientific Reports.

[2]  C. Pittenger,et al.  Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS , 2016, Journal of immunology research.

[3]  Robert E. Schmidt,et al.  A complement–microglial axis drives synapse loss during virus-induced memory impairment , 2016, Nature.

[4]  Ben A. Barres,et al.  Complement and microglia mediate early synapse loss in Alzheimer mouse models , 2016, Science.

[5]  Michelle K. Cahill,et al.  Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation , 2016, Cell.

[6]  James R. Tribble,et al.  Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma , 2016, Molecular Neurodegeneration.

[7]  Grayson O. Sipe,et al.  Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex , 2016, Nature Communications.

[8]  Shaomin Li,et al.  Complement C3-Deficient Mice Fail to Display Age-Related Hippocampal Decline , 2015, The Journal of Neuroscience.

[9]  R. Chung,et al.  In vivo characterization of microglial engulfment of dying neurons in the zebrafish spinal cord , 2015, Front. Cell. Neurosci..

[10]  C. Greer,et al.  Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons , 2015, Proceedings of the National Academy of Sciences.

[11]  Diego Diez,et al.  Neuronal exosomes facilitate synaptic pruning by up-regulating complement factors in microglia , 2015, Scientific Reports.

[12]  Chang Liu,et al.  Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. , 2012, Developmental cell.

[13]  L. Belluscio,et al.  Odorant receptors in the formation of the olfactory bulb circuitry. , 2012, Physiology.

[14]  Ben A. Barres,et al.  Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner , 2012, Neuron.

[15]  M. Giustetto,et al.  Synaptic Pruning by Microglia Is Necessary for Normal Brain Development , 2011, Science.

[16]  C. Gross,et al.  Microglia in development: linking brain wiring to brain environment. , 2011, Neuron glia biology.

[17]  Ania K. Majewska,et al.  Microglial Interactions with Synapses Are Modulated by Visual Experience , 2010, PLoS biology.

[18]  G. Enikolopov,et al.  Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. , 2010, Cell stem cell.

[19]  Leonardo Belluscio,et al.  Continuous Neural Plasticity in the Olfactory Intrabulbar Circuitry , 2010, The Journal of Neuroscience.

[20]  D. Restrepo,et al.  Disorganized olfactory bulb lamination in mice deficient for transcription factor AP-2ɛ , 2009, Molecular and Cellular Neuroscience.

[21]  C. Nüsslein-Volhard,et al.  Live Imaging of Neuronal Degradation by Microglia Reveals a Role for v0-ATPase a1 in Phagosomal Fusion In Vivo , 2008, Cell.

[22]  L. Belluscio,et al.  Charting Plasticity in the Regenerating Maps of the Mammalian Olfactory Bulb , 2008, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[23]  John D. Lambris,et al.  The Classical Complement Cascade Mediates CNS Synapse Elimination , 2007, Cell.

[24]  J. Cloutier,et al.  Requirement for Slit-1 and Robo-2 in Zonal Segregation of Olfactory Sensory Neuron Axons in the Main Olfactory Bulb , 2007, The Journal of Neuroscience.

[25]  Leonardo Belluscio,et al.  Activity-Dependent Plasticity in the Olfactory Intrabulbar Map , 2006, The Journal of Neuroscience.

[26]  Leonardo Belluscio,et al.  Olfactory experience accelerates glomerular refinement in the mammalian olfactory bulb , 2006, Nature Neuroscience.

[27]  B. Key,et al.  The sorting behaviour of olfactory and vomeronasal axons during regeneration , 2006, Journal of Molecular Histology.

[28]  F. Helmchen,et al.  Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo , 2005, Science.

[29]  Peter Mombaerts,et al.  Postnatal Refinement of Peripheral Olfactory Projections , 2004, Science.

[30]  P. Mombaerts,et al.  A Contextual Model for Axonal Sorting into Glomeruli in the Mouse Olfactory System , 2004, Cell.

[31]  Lawrence C Katz,et al.  Functional Topography of Connections Linking Mirror-Symmetric Maps in the Mouse Olfactory Bulb , 2003, Neuron.

[32]  Lawrence C. Katz,et al.  Odorant receptors instruct functional circuitry in the mouse olfactory bulb , 2002, Nature.

[33]  M. Ehlers,et al.  CR3: a general purpose adhesion-recognition receptor essential for innate immunity. , 2000, Microbes and infection.

[34]  B. Key,et al.  Development of P2 Olfactory Glomeruli in P2-Internal Ribosome Entry Site-Tau-LacZ Transgenic Mice , 1999, The Journal of Neuroscience.

[35]  R. M. Costanzo,et al.  Regeneration of olfactory receptor cells. , 1991, Ciba Foundation symposium.

[36]  R. Levine,et al.  Regeneration of olfactory axons and synapse formation in the forebrain after bulbectomy in neonatal mice. , 1978, Proceedings of the National Academy of Sciences of the United States of America.