Duan, Shumin

MacVicar, Brian A.

Stevens, Beth

Wu, Long-Jun

Neural Plasticity

Long-Jun Wu

Beth Stevens

Shumin Duan

Brian A. MacVicar

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Microglia in Neuronal Circuits

Harvard University - DASH 

 Microglia in Neuronal Circuits  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Wu, Long-Jun, Beth Stevens, Shumin Duan, and Brian A.MacVicar. 2013. “Microglia in Neuronal Circuits.” NeuralPlasticity 2013 (1): 586426. doi:10.1155/2013/586426.http://dx.doi.org/10.1155/2013/586426.Published Version doi:10.1155/2013/586426Accessed February 19, 2015 3:12:38 PM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879576Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAAHindawi Publishing CorporationNeural PlasticityVolume 2013, Article ID 586426, 3 pageshttp://dx.doi.org/10.1155/2013/586426EditorialMicroglia in Neuronal CircuitsLong-Jun Wu,1 Beth Stevens,2 Shumin Duan,3 and Brian A. MacVicar41 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA2Children’s Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA3Department of Neurobiology, Zhejiang University School of Medicine, 866 Yu Hang Tang Road, Hangzhou, Zhejiang 310058, China4Department of Psychiatry, University of British Columbia, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5Correspondence should be addressed to Long-Jun Wu; lwu@dls.rutgers.eduReceived 1 December 2013; Accepted 1 December 2013Copyright © 2013 Long-Jun Wu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.1. IntroductionMicrogliacompriseauniquesubsetofglialcellsastheprinci-palbrainimmunecellsandareactivelyengagedinphysiolog-ical and pathological brain functions. Unlike other residentneural cells that are of neuroectodermal origin, microgliaare of mesodermal origin and invade the neuroepitheliumat early embryonic stages. As resident immune responsecells, microglia are extremely sensitive to almost any braindisturbance.Therefore,microgliaaretraditionallyrecognizedfor their immune functions during acute brain injury, suchas bacterial meningitis, ischemic stroke, and spinal cordinjury, as well as chronic neurological disorders, such asAlzheimer’s disease, Parkinson’s disease, multiple sclerosis,and neuropathic pain. Recently, the role of microglia inneurodevelopmentand neural plasticity in the healthybrainshas gained tremendous attention. These exciting results raisean intriguing possibility that microglia can integrate into theneuronal circuits in the healthy and diseased brain.In support of this notion, it is emerging that microgliahave remarkably dynamic processes and are frequentlyinteracting with neurons and synaptic elements. Throughthese interactions, microglia may monitor neuronal/synapticactivities and thus survey the microenvironment in thebrain. Indeed, recent studies have apparently shown thatmicroglia function in neuronal circuits by playing diverseroles in neural development, behavior, and pathology in thebrain. Therefore, microglia research has changed the waywe think about neuronal network/plasticity and increasedour understanding of brain diseases associated with abnor-mal microglia. Contributions to this special issue providea snapshot of microglial function in the healthy and diseasedbrain and propose a fundamental role of microglia in neu-ronal circuits.2. Microglia in the Healthy BrainThe vivid observation of microglia in the healthy brainthrough in vivo imaging in 2005 was a breakthrough inmicroglia research. For the first time, researchers witnessedthat microglia are extremely motile and their processes areconstantly monitoring the microenvironment without anypathological insults. Subsequently, studies were boomingt of o c u so nt h ep o t e n t i a lr o l eo fm i c r o g l i ai nt h eh e a l t h ybrain, including synaptic pruning in the development andregulation of synaptic transmission/plasticity. On the otherhand, several lines of evidence have also indicated theneuronal control of microglial activities under physiologicalconditions. In this special issue, U. B. Eyo and L. J. Wuhighlight recent findings on this bidirectional interactionb e t w e e nn e u r o n sa n dm i c r o g l i a .Th er e v i e ws u m m a r i z e dhow microglia signal to neurons through direct physicalcontact or signaling molecules such as fractalkine, com-pliment, and DAP12, as well as how microglial activity ismodulated by neuronal signals including classic neurotrans-mitters and chemotactic signals. In addition, the authorsdiscussed studies of microglial depletion as an approach tounderstand microglial importance in neuronal development,function, and maintenance. This review on bi-directionalmicroglial-neuronalcommunicationprovidesanoverviewofhow microglia are integrated into neuronal circuits in thehealthy brain.2 Neural PlasticityRecentstudieshaverevealedasurprisingroleofmicrogliain the structural remodeling of neuronal circuits by usingtheir immune abilities in the healthy brain. For example,microglia were demonstrated to eliminate neuronal precur-sors, synaptic elements, and newborn cells during adult neu-rogenesis.Inthisspecialissue,Z. ˇ Siˇ skov´ aandM.-E.Tremblayfurther zoom in on the microglial function in the neuronalcircuits and review recent studies on the microglia-synapseinteractions in the mature healthy brain. The focused reviewdiscussestheemergingrolesofactivity-dependentmicroglialelimination of synaptic elements (dendritic spines and axonterminals) notably by phagocytosis. This microglia-synapseinteraction enables synaptic pruning and thus might becrucialfortheexperience-dependentremodelingofneuronalcircuits in the mature brain as well as during normal aging.In addition to structural remodeling, microglia areable to modulate synaptic activities and plasticity. Evidencefrom imaging, cellular, and electrophysiological approachesindicates that microglia affect synaptic maturation duringdevelopment as well as the acute and dynamic regulationof neuronal activity in the mature healthy brain. In thisspecial issue, S. E. Tsirka and colleagues review the recentstudies on microglia as an active player in the regulationof synaptic activities and suggest that microglia are animportant contributor to the potential quad-partite synapse.Thereviewsummarizedsomeinterestingmechanismsunder-lying microglial regulation of synaptic activities and synapticnumbers: the proteases secreted from microglia to remodelextracellular matrix, the release of microvesicles (shed vesi-cles or ectosomes) derived from microglia, and connexinsand large pore channels as a way by which microglia interactdirectly with neurons. A plethora of potential messengersmediatethecommunicationbetweenmicrogliaandneurons,including cytokines, purines, glutamate, prostaglandins, andnitricoxide.Inthisspecialissue,F.FerriniandY.DeKoninckparticularly discuss a unique microglial signaling molecule,brain-derived neurotrophic factor (BDNF), in controllingneuronal excitability in both physiological and pathologicalconditions.3. Microglia in the Diseased BrainResting microglia rapidly transform into an activated state inmost pathological processes, including host defense againstinfectious organisms, autoimmune inflammation, ischemia,trauma, chronic pain, and neurodegeneration. Activationof microglia is accompanied by changes in morphology,upregulation of immune surface antigens, production ofcytotoxic or neurotrophic molecules, and phagocytosis ofpathogens, degenerating cells, and inflammatory debris.Although microglial activation is well documented in avariety of neurological disorders, the definitive beneficial ordetrimental roles of microglia in these diseases remain con-troversial. The consensus is that microglia play different rolesb a s e do nt h et e m p o r a la n ds p a t i a lc o n t e x to fb r a i nd i s e a s e s ;the proinflammatory cytotoxic aspects of activated microgliamight be important at an early stage while microglia’s anti-inflammatory effects become more prominent later duringtissue repair. Nevertheless, microglia evidently respond andevencausetheabnormalityofneuronalcircuitsunderpatho-logical conditions.Neuronal cell death, loss of synapses, and neuroinflam-mation are hallmarks and emerged as a major correlateof cognitive decline in neurodegenerative disorders. In thisspecial issue, Z. ˇ Siˇ skov´ a and M.-E. Tremblay extend thediscussion of microglia-synapse interaction to the contextof neurodegenerative disorders, such as Alzheimer’s disease,Parkinson’s disease, and prion diseases. Chronic microglialactivation under these pathological conditions likely con-tributes to synaptic dysfunction and elimination, therebyexacerbating neurodegeneration. Richardson and Hossainspecifically review recent studies on the role of microglia inParkinson’sdisease.Activatedmicrogliaandsubsequentneu-roinflammation have been consistently associated with thepathogenesis of Parkinson’s disease. Therefore, the authorsdiscuss the potential of targeting microglia to reduce neu-roinflammation, with particular focus on microglial ionchannels as novel therapeutic targets for neuroprotection inParkinson’s disease.The physiology of microglia in the spinal cord is lesswell studied; however, there is strong evidence of spinalcord microglia in the genesis of chronic pain. In this specialissue, R.-R. Ji and colleagues discuss the microglial acti-vation through the mitogen-activated kinase pathways, aswell as microglial mediators (tumor necrosis factor-alpha,interleukin-1 beta, and BDNF) in regulating synaptic plastic-ityofpaincircuitsinthespinalcordinneuropathicpain.Fer-rini and De Koninck focus specifically on microglial BDNFin multiple neurological conditions, including epilepsy, drugaddiction, spinal cord injury, and neuropathic pain. Inparticular, microglial BDNF in the spinal cord is wellestablished in neuronal disinhibition in neuropathic painin the following signaling cascade: the BDNF activationof neuronal TrkB receptor, downregulation of the K+-Cl−cotransporter KCC2, disruption of Cl− homeostasis, andhence the reduced strength of GABAA-a n dgl y c i n er ec e p t o r -mediatedinhibition.Spinalcordinjurytriggersinflammationwith activation of innate immune responses, where bothmicroglia and macrophages are activated and accumulated.In this special issue, Y. Ren and W. Young review thebeneficial mechanisms of macrophages on spinal cord injuryby inhibition of proinflammatory responses, stimulation ofangiogenesis,secretionofneurotrophicfactors,andclearanceof myelin debris in the injured spinal cord, providing arationale of macrophage-based therapies for spinal cordinjury. Therefore, insights into the communication betweenmicroglia/microphages and neurons in the spinal cord willnot only further our understanding of microglia function inneuronal network but may also lead to novel therapeutics forameliorating a wide array of neural dysfunctions, includingchronic pain and spinal cord injury.4. Concluding RemarksTh i ss p e c i a li s s u es u m m a r i z e sab r o a dr a n g eo ft o p i c so nmicroglia in neuronal circuits in both the healthy anddiseased brains, with particular emphasis on bidirectionalmicroglia-neuron communication, microglial remodelingNeural Plasticity 3of synapse, microglial regulation of synaptic activities,microglial BDNF signaling, microglia in neurodegenerationsuch as Parkinson’s disease, spinal microglia in neuropathicpain, and macrophages in the spinal cord injury. In spiteof the controversy, it is clear that microglia are importanta n di nn e e do ff u r t h e rs t u d yi nt h ec e n t r a ln e r v o u ss y s t e m .We hope that papers published in this special issue willserve to increase the scientific knowledge on microglialfunctioninthebrainandoffernewperspectivesonthepoten-tial therapeutics targeting microglia/macrophages in variousneurological disorders. The past few years have witnessedmany important discoveries in the microglia field; however,there is still a long road ahead for exploring the mechanismsunderlying microglial function in neuronal circuits at boththe molecular and system levels.Long-Jun WuBeth StevensShumin DuanBrian A. MacVicar

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Microglia in Neuronal Circuits

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