review article microglia control neuronal network...

Hindawi Publishing CorporationNeural PlasticityVolume 2013 Article ID 429815 11 pageshttpdxdoiorg1011552013429815

Review ArticleMicroglia Control Neuronal Network Excitabilityvia BDNF Signalling

Francesco Ferrini1 and Yves De Koninck23

1 Department of Veterinary Sciences University of Turin Grugliasco 10095 Turin Italy2 Institut Universitaire en Sante Mentale de Quebec Quebec QC Canada G1J 2G33Department of Psychiatry and Neuroscience Universite Laval Quebec QC Canada G13 7P4

Correspondence should be addressed to Yves De Koninck yvesdekoninckneuroulavalca

Received 8 June 2013 Accepted 28 July 2013

Academic Editor Long-Jun Wu

Copyright copy 2013 F Ferrini and Y De KoninckThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural networkexcitability such as epilepsy and neuropathic pain While a series of potential messengers have been postulated as substrates of thecommunication between microglia and neurons including cytokines purines prostaglandins and nitric oxide the specific linksbetweenmessengers microglia neuronal networks and diseases have remained elusive Brain-derived neurotrophic factor (BDNF)released bymicroglia emerges as an exception in this riddle Here we review the current knowledge on the role played bymicroglialBDNF in controlling neuronal excitability by causing disinhibitionThe efforts made by different laboratories during the last decadehave collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release ofBDNF frommicroglia the downstream TrkB-mediated signals in neurons and the biophysical mechanism by which disinhibitionoccurs via the downregulation of the K+-Clminus cotransporter KCC2 dysrupting Clminus homeostasis and hence the strength of GABAA-and glycine receptor-mediated inhibitionThe resulting altered network activity appears to explain several features of the associatedpathologies Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approachfor ameliorating a wide array of neural dysfunctions

1 Introduction

Once simply considered as the ldquoguardiansrdquo of the cen-tral nervous system (CNS) microglia have more recentlyemerged as key players in regulating neuronal networkexcitability Indeed physical and chemical alterations inthe extracellular environment promote the synthesis andrelease of several microglia-derived molecules which inturn shape neuronal circuit function The effects of suchmicroglia-neuron interactions were found to be critical inthe course of different central disorders and in particularseminal studies provided significant evidence for a role ofmicroglia in the pathogenesis of seizures (for review see[1 2]) which was associated with increased glutamatergictransmission through the potentiation of NMDA receptor-mediated activity [3] However from a theoretical point ofview raising network excitability can be equally achievedthrough increasing excitatory inputs or removing inhibitory

ones In fact unmasking silent interconnections can be betterachieved through disinhibition than enhanced excitationFurthermore disinhibition has been shown as an upstreamsubstrate of activity-dependent enhancement of excitation inseveral plasticity paradigms [4ndash7] Thus in addition to theglutamatergic hypothesis it can be postulated that microgliaalter neuronal excitability by affecting synaptic inhibitionThis hypothesis has been explored during the last decade andthe results of several investigations have uncoveredmolecularmechanisms underlying microglia-mediated disinhibition

Synaptic inhibition in central neurons is mediated by 120574-amino-butyric acid (GABA) and glycine (Gly) which activateionic channels (GABAAR and GlyR) permeable to anionsnamely chloride (Clminus) and bicarbonate (HCO

3

minus) Underphysiological conditions Clminus flows inwardly andHCO

3

minus out-wardly along with their electrochemical gradient Clminus contri-bution is by far the more conspicuous and consequently thereversal potential of GABAglycine (EGABAEgly) in adult

2 Neural Plasticity

neurons is set below the resting potential (Vr) near the Clminusequilibrium (ECl) It follows that when GABAARGlyR areactivated Clminus produces a net hyperpolarization Although inprinciple correct this brief summary of the ionicmechanismsof synaptic inhibition provides a quite static representation ofGABAGly-mediated transmission and importantly does nottake into account that EGABAEGly and Vr being only fewmillivolts apart even a small change in anion concentrationsmay have a profound functional impact [8 9] In this respectthe critical variable is represented by the intracellular Clminusconcentration and the critical property is the capacity ofthe cell to maintain this concentration low In the eventthat intracellular Clminus rises it follows that (i) EGABAEGlyshifts toward or beyond Vr (ii) the Clminus gradient acrossthe membrane collapses and (iii) the previously negligibledepolarizing HCO

3

minus current becomes more relevant Onthe whole an increase in the intracellular Clminus concentrationweakens the strength of GABAGly-mediated inhibition orin the extreme case turns it into paradoxical excitation [10]

How do neurons control intracellular Clminus concentrationChloride homeostasis in cells is maintained by a group ofmembrane carriers known as cation-chloride cotransporters(CCCs [11 12]) The K+-Clminus cotransporter 2 KCC2 is themain CCC isoform expressed in central neurons [13 14]KCC2 extrudes Clminus following the K+ gradient and its activitytypically maintains a low intracellular Clminus concentrationwhich is the prerequisite for an effectiveGABAGly-mediatedinhibition Now KCC2 activity is not static but it can be pro-foundly modulated by different physiological or pathologicalchallenges The most spectacular example of such plasticityhas been extensively described during development [14ndash16] KCC2 is little expressed in prenatal and early postnatalbrains but during maturation it undergoes a developmentalincrease which parallels the switch in GABAGly-mediatedtransmission from excitatory to inhibitory [14] These mech-anisms are thought not only to play a pivotal role in theactivity-dependent development of central synapses duringCNS maturation [17] but also to favor a proper wiring bytriggering spontaneous rhythmic activity in motor networks[18] and to promote synaptic integration of new born neuronsin those area of the brain in which adult neurogenesis occurs[19 20] On the other hand reduction of KCC2 activityhas been associated with several neurological diseases andconditions originally epilepsy and neuropathic pain [10]and more recently motor spasticity [21] stress [22] andschizophrenia [23 24] Several lines of evidence accumulatedduring the last decade have indeed demonstrated that theincrease in excitability in these pathological conditions canbe largely explained by a loss of inhibition and KCC2 hasbeen recognized as a keymolecular target underlying this loss[25 26]

The findings in recent years that KCC2 can be dynam-ically modulated by several intercellular signaling pathwayshave been particularly interesting [4] the most prevalentbeing brain-derived neurotrophic factor (BDNF) signalingonto neuronal TrkB receptors [27ndash31] Even more intriguingis the finding that in certain conditions BDNF in the CNS isnot only released by neurons but also bymicroglia [32] In thisreview we summarize and discuss the more relevant findings

supporting the role of microglia in conditioning KCC2 func-tion as well as consequently inhibitory neurotransmissionthrough the release of BDNF Several convergent findingsuncover a canonical signaling mechanism by which theimmune system can control neuronal network excitability byregulating the strength of inhibition

2 Role of BDNF in the Control ofKCC2 Function

BDNF is a neurotrophin with important functions in neu-ronal survival and differentiation However beyond its clas-sical neurotrophic role BDNF is directly involved in thecontrol of neuronal activity and synaptic plasticity as a neuro-modulator [33ndash35] These functions are described in severalareas of the CNS such as hippocampus [36] cortex [37]amygdala [38] cerebellum [39] and spinal cord [34] and areinvolved in different forms of plasticity [40 41] Althoughinitial studies mainly focused on glutamatergic synapsesthe effects of BDNF on GABAergic transmission have latelyreceived increasing attention [40] Interestingly early workon these effects performed in the rat hippocampus yieldeda number of conflicting results unveiling a more complexpicture than expected Indeed in juvenile rodents BDNFwas found to favor a substantial depression of GABAergictransmission via either pre- or postsynaptic mechanisms[42 43] conversely studies in immature neurons showedan overall potentiating effect [44 45] To explain such adiscrepancy it was hypothesized that the effect of BDNF ontoGABAergic transmission in hippocampal neurons might bedevelopmentally regulated in parallel with the switch inGABAergic transmission from excitatory to inhibitory [46]Thus BDNF depresses GABAergic transmission in matureneuronswhenGABA is inhibitory andpotentiates it in imma-ture neurons when GABA is depolarizing favoring activity-dependent synapse formation which has been relayed toGABA-mediated Ca2+ entry in developing neurons [37 4446] The fact that the changes in BDNF effects on GABA-mediated transmission are coincident with the developmen-tal switch in GABAergic current polarity raised the questionof whether BDNF has an effect on KCC2 function andorexpression This was indeed demonstrated by Rivera andcolleagues [29 30] The authors provided evidence thatin hippocampal slices BDNF rapidly downregulates KCC2expression through the BDNF preferred receptor TrkB (tyro-sine kinase B receptor) thus reducing neuronal Clminus extrusioncapacity [29]The effect required the activation of two down-stream cascades involving src homology 2 domain containingtransforming proteinFGF receptor substrate 2 (ShcFRS-2)and phospholipase C 120574- (PLC120574-) cAMP response element-binding protein signaling respectively [30] Interestinglythe activation of the Shc pathway alone was surprisinglyfound to promote the upregulation of KCC2 which mightelegantly explain the opposite effects of BDNF across braindevelopment based on the specific intracellular pathwaysinvolved [30] One important point of this study is that themembrane level of KCC2 undergoes a fast turnover rate andthis turnover is accelerated by exogenous BDNF or by an

Neural Plasticity 3

increased neuronal activity during which BDNF is released[30] A logical consequence is that such a fast regulationof KCC2 activity which happens in few hours or less isnot compatible with the physiological time course requiredfor altering gene expression and a number of alternativemechanistic models have been proposed including proteinphosphorylation trafficking and quaternary structure [47]In particular KCC2 activity and membrane localizationseem to depend on the tyrosine phosphorylation level andBDNF has been shown to promote KCC2 dephosphoryla-tion which in turn reduces surface protein expression [48]Thus KCC2 phosphorylation influences protein traffickingby either increasing endocytosis or reducing insertion [48]Alternatively KCC2 transport activity has been directlycorrelated with the capacity of the protein to form oligomersat the membrane level [49] Thus Clminus extrusion capacity isimproved if KCC2 is organized in oligomers and an increasedoligomersmonomers ratio parallels the KCC2 upregulationduring development [49] Interestingly KCC2 clustering isstrongly reduced in the presence of a point mutation on theKCC2 tyrosine phosphorylation site suggesting that phos-phorylation and oligomerization might simply be differentparts of the same process controlling the transporter activity[50] Finally KCC2 activity can also be rapidly affected bythe activation of the Ca2+-dependent protease calpain [11]and these pathways may be under the control of BDNFTrkBsignaling [51]

Altogether these findings provided clear evidence thatClminus homeostasis can be rapidly regulated by an extracellularsignal such as BDNF thus inducing short- or long-termchanges in neuronal activity that cannot be simply explainedin terms of classical synaptic plasticity but rather as a novelform of ldquoionic plasticityrdquo [16]

After the initial studies on the effects of BDNF on Clminushomeostasis in CA1 pyramidal neuron of the hippocampus[29 30] similar mechanisms were subsequently observed indifferent regions across the CNS including the spinal dorsalhorn [27] and ventral horn [21] the ventral tegmental area[52] the cortex [53 54] and the cerebellum [39] Thesefindings attracted attention to the fact that BDNF may playa pivotal role as a regulator of neuronal Clminus homeostasis inthe brain and by ricochet of inhibition and hence neuronalnetwork excitability

3 Microglia Are a Central Source of BDNF

The expression of BDNF in synaptic vesicles and its synapticrelease from different neuronal populations [34 55] sup-port the role of the neurotrophin in activity-dependentdownregulation of KCC2 [30] However BDNF is not onlyexpressed by neurons but is also found in astrocytes [56]and microglia [32] Microglial BDNF was first shown inmicroglia cultures [57 58] and soon confirmed in differentregions of the CNS during the course of various neurologicaldisorders such as viral encephalitis [59] traumatic injury[60 61] ischemia [62] multiple sclerosis [63] Parkinsonrsquosdisease [64] neuropathic pain [27] and spasticity [21] Thatmicroglia are a potential source of BDNF is a crucial point to

predict the role of the neurotrophin in neurological disordersIndeed microglia primary function is to sense and reactto alterations of the extracellular milieu with a protectiveand defensive role In the presence of factors signalingpotentially harmful microglia undergo morphological andfunctional alterations collectively identified under the termof ldquomicroglia activationrdquo and depending on the signalingpathways involved this process may lead to secretion ofspecificmessengers including BDNF [65] Once released theneurotrophin in turn sculpts neuronal circuit excitability viathe signaling cascade described above

The synthesis and release of BDNF in microglia appearto be tightly associated with the purinergic receptor P2X4R[65ndash67] Purinergic receptors are endogenously activated byATP (Adenosine-51015840-triphosphate) which is typically storedin the cytoplasm of neuronal and nonneuronal cells andreleased in the extracellular space following tissue damage[68] Alternatively ATP may be released by neurons [69]or astrocytes [70] Microglia sense extracellular ATP troughdifferent types of purinergic receptors [68] such as P2Y12Rswhich can detect tiny gradient of extracellular ATP andpromote microglia migration [71 72] or P2X7Rs whichtrigger morphological changes in microglia from a restingto an activated state [73] Microglial P2X4Rs instead donot appear to be involved in the morphological alterationsleading to the activated phenotype but rather their involve-ment is a functional consequence ofmicroglia activation [65]Indeed P2X4Rs are normally expressed at negligible levelsin resting microglia and they need to be upregulated topromote BDNF synthesis and release [65] Which externalfactors are involved in the upregulation of P2X4R in activatedmicroglia is still a matter of debate Chemokines releasedfrom injured neurons such as CCL2 and CCL21 have beenregarded as potential inductors of P2X4R expression [7475] In particular CCL21 application in vivo and in vitrostrongly promoted P2X4R upregulation in spinal microglia[74] Interestingly in both CCL21 [74] and P2X4R [65] defi-cient mice microglia activation is not compromised whichimplies a mechanistic separation between the morphologicalchanges and the subsequent downstream effects Also CCL2which instead plays an important role in microglia activationafter injury [76 77] has been suggested to participate inthe P2X4R upregulation process however CCL2 does notseem involved in de novo expression of the protein butrather it has been suggested to promote P2X4R traffickingfrom intracellular stores to the cell membrane [75] Finallya few nonneuronal endogenous molecules have been alsoidentified as potential inductors of P2X4R in microglianamely the proinflammatory cytokines INF-120574 [78] the mastcell-derived tryptase activated PAR2 [79] and fibronectina component of the extracellular matrix [80 81] At thenuclear level the interferon regulatory factor 8 (IRF8) hasbeen recently proposed as a key transcription factor involvedin the upregulation of P2X4Rs in activated microglia [82]

Once upregulated P2X4Rs can efficiently respond toextracellular fluctuation in ATP concentration and initiatesthe intracellular cascade leading to BDNF synthesis and

4 Neural Plasticity

release Being particularly highly Ca2+ permeable P2X4channels cause a significant Ca2+ influx and the downstreamactivation of Ca2+-dependent intracellular pathways amongwhich the phosphorylation of p38 MAP kinase which isdirectly involved in the synthesis and release of BDNF [67]In addition Ca2+ influx through P2X4Rs is also necessary todirectly facilitate the release of BDNFby acting on the vesicle-releasing machinery which is typically an NSF-attachmentprotein-(SNARE-) mediated exocytosis [67] Alternativepathways (ie ERK12) have been also suggested to promoteBDNF synthesis in culturedmicroglia [83 84] however thesehypotheses need to be properly confirmed in vivo

4 The Special Case of Neuropathic Pain

Based on the findings outlined above the following con-clusions can be drawn (1) various extracellular signals mayactivate microglia and upregulate P2X4Rs (2) P2X4R activa-tion triggers the release of BDNF from microglia (3) BDNF-TrKB signaling alters KCC2 function leading to a reducedClminus extrusion capacity which dampensGABAARGlyRmedi-ated inhibition Assuming that all these events happen insequence one should expect that microglia under certainfunctional states influence synaptic inhibitionThis is indeedthe case of neuropathic pain [66] Nociceptive transmis-sion is normally conveyed to higher centers through spinalnociceptive pathways In the most simple configuration thisinvolves peripheral neurons located in the dorsal root gangliawhich contact second-order neurons in the spinal dorsalhorn and a spinal projection neurons which transmits theinformation to the thalamus In the spinal dorsal horn paintransmission is controlled by a network of local inhibitoryinterneurons which assure the separation of nociceptivesensory pathways from nonnociceptive sensory pathways byreleasingGABA andGly [85] Indeed a spinal administrationof GABAAR or GlyR antagonists induces tactile allodynia[86 87] a clinical condition in which innocuous stimuli areperceived as painful Tactile allodynia is a classical symptomof neuropathic pain and indicates an erroneous encodingof low threshold stimuli through the nociceptive channelSeveral causal events have been postulated to promote spinaldisinhibition including presynaptic mechanisms affectingthe amount of transmitter released and intracellular path-ways regulating postsynaptic GABA and glycine receptorfunctionexpression [7] In our laboratory we found thataltered Clminus homeostasis in the superficial spinal dorsal hornappears as a key mechanism underlying neuropathic painsymptoms [88] and that this alteration results from therelease of BDNF from microglia [27] Microglia had alreadybeen implicated in the pathogenesis of neuropathic pain[89ndash91] and in particular the upregulation of P2X4Rs inmicroglia was early identified as a crucial step in the centralsensitization process [92] P2X4Rs are in fact necessary forthe development of mechanical allodynia after nerve injuryand are required for the release of BDNF from microglia[65 67] BDNF in turn binds TrkB receptors in neurons of thesuperficial dorsal horn thus compromising KCC2 function

and altering Clminus homeostasis [27] Blocking the microglia-to-neuron cascade at any level reverses established allody-nia in neuropathic animals by restoring spinal inhibitoryGABAergicglycinergic transmission [27 28] Subsequentstudies have provided additional evidence that this formof spinal disinhibition happens in a different model ofpathological pain such as spinal cord injury [93] diabetes-induced neuropathy [94] and orofacial pain [95] Moreoverwe have very recently shown that the pain hypersensitivityinduced by morphine (better known as morphine-inducedhyperalgesia) is mediated by the same P2X4Rs-BDNF-TrkB-KCC2 cascade thus recapitulating the sequence of eventsdescribed in neuropathic pain [28] In the latter study weused a transgenic mouse in which BDNF expression wasgenetically ablated in microglia only and we showed thatwithout microglial BDNF morphine hyperalgesia does nottake place The involvement of spinal microglia in thisspecific form of hypersensitivity is due to the expression ofopioid receptors inmicroglia [84] whose activation promotesP2X4Rs [28] In turn morphine appears to act on microgliavia a nonopioid receptor-dependent pathway to enable BDNFrelease upon P2X4Rs activation [28]

In conclusion ten years of investigations on the spinalmechanisms of nociceptive transmission have provided com-pelling evidence that neuropathic pain critically dependson microglia-to-neuron signals which alter GABAglycine-mediated inhibition

5 Microglia-BDNF-KCC2 Signaling in thePathogenesis of Multiple NeurologicalConditions

The microglia-to-neuron communication discovered in thedorsal horn of the spinal cord can be virtually replicated in allthose regions of the CNSwhere functional TrkB receptors areexpressed andmay play a role in the development of multiplecentral disorders [10] Accumulating evidence in recent yearssupports this hypothesis

In the spinal motor system a TrkB-KCC2 interaction hasbeen described in motoneurons following spinal cord injury[21] Here the reduced Clminus extrusion capacity due to thedownregulation of KCC2 was associated with hyperreflexiaand spasticity a clinical condition burdening a large numberof patients with spinal trauma [96]The authors did not inves-tigated the origin of BDNF in their model howevermicrogliaare clearly involved in the pathophysiology resulting fromspinal cord injury [97] and a role for microglial P2X4Rs hasalso been envisaged [98] suggesting a microglial BDNF link

In the brain alterations in Clminus homeostasis have beenshown to underlay epilepsy in animals and humans [99]Based on experiments in vitro on hippocampal slices [2930] TrkB-KCC2 signaling was proposed as the molecularmechanism underlying hyperexcitability in epilepsy [30]In this model however KCC2 downregulation was shownto be activity dependent thus implying a neuronal sourceof BDNF whose release is directly related to the level ofnetwork excitability On the other hand epilepsy has mul-tiple etiologies and might develop in different brain areas

Neural Plasticity 5

A role for microglia can be therefore predicted in thosepathological conditions which imply a neuronal damageand the subsequent reorganization of synaptic function asin the case of a traumatic event [100] Indeed a TrkB-dependent downregulation of KCC2 has also been describedin traumatic brain injury [101] a condition in which neuronaldeath and inflammation clearly promote the activation ofmicroglia [102] Interestingly in animal models of traumaticbrain injury microglia were found to express P2X4Rs andphosphorylated p38 [103 104] which is known to be themainupstream signal for BDNF synthesis and release in microglia[67]

Finally a BDNF-mediated impairment of Clminus homeosta-sis has been shown to underlie the central mechanisms ofopiate dependence in the ventral tegmental area (VTA) [52]Although the main source of BDNF remains here elusivechronic exposure to opioids is known to activate microgliaand to induce the synthesis of BDNF [28 84] which in turnimpairs Clminus homeostasis in central neurons [28] In additionit has recently been described that functionalmodifications inmicroglia are involved in mechanisms of opiate dependencein the nucleus accumbens where the early exposure tomorphine in young rats was shown to influence drug-seekingbehavior in adulthood increasing the risk of drug-inducedreinstatement [105]

Taken together these evidence indicate that BDNF-TrkBsignaling drives disinhibition by targeting KCC2 functionSuch an effect does not directly depend on the source ofBDNF (neuron astrocytes or microglia) but rather on theintracellular pathways linking TrkB to KCC2 [29] This isexemplified in immature neurons where BDNF-TrkB signal-ing rather than causing KCC2 downregulation stimulatesthe synthesis of KCC2 and favors the developmental switch ofGABAergic transmission from excitatory to inhibitory [106]In contrast microglial BDNF has gained special attentionas underlying neurological diseases in adult tissue and thisis mainly due to the specific role played by microglia inthe CNS Indeed microglia-driven disinhibition via BDNF-TrkB signaling can be regarded as a peculiar consequence ofmicroglial reaction to injury or to certain pharmacologicaltreatments potentially occurring in different areas of theCNS The ldquopathologicalrdquo consequences of such process areusually dramatic leading for instance to an altered noci-ceptive behavior or to seizure It remains enigmatic whatthe normal ldquophysiologicalrdquo meaning of the release of BDNFfrommicroglia and the subsequent downregulation of KCC2is The primary role of microglia is in fact to react inresponse to a variety of external challenges supposedly withthe aim of protecting neurons In this context the releaseof BDNF can be considered as a part of a neuroprotectivestrategy being neurotrophins classically involved in neuronalsurvival process [107] A neuroprotective and reparative rolefor microglial BDNF has indeed been postulated duringthe course of encephalitis [59] brain ischemia [62] andtraumatic injury [60] Interestingly the posttraumatic lossof KCC2 in mature neurons induced by BDNF and thesubsequent GABA-mediated depolarization was found nec-essary for neuronal survival of injured neurons a mecha-nism which is strongly reminiscent of the trophic effect of

excitatory GABA during CNS development [101] In contrastthe central inflammatory reaction in the spinal dorsal hornfollowing peripheral nerve injury appears to be substantiallymaladaptive and detrimental Indeed the activation of spinalmicroglia following nerve injury produces a release of BDNFonto spinal neurons which are not directly injured The maineffect of microglial activation in this case is thus the sup-pression of spinal inhibition and the activation of nociceptivepathways leading to the clinical development of neuropathicpain [27] Microglia therefore appear as an ambiguous actorin some cases protective and in other cases having deleteriousactions [108] An accurate prediction of the balance betweenneuroprotection and neurotoxicity appears thus important tounderstand how microglia intervene in diseases to developappropriate therapeutic strategies

Yet regardless of the positive or negative outcomeof microglia action on neuronal survival and repair theactivation of the P2X4R-BDNF-TrkB-KCC2 cascade allowsmicroglia to critically control network excitability and tounmask hiddenneuronal circuits that are normally kept silentby the physiological Clminus-mediated inhibition (Figure 1) [109]

6 Future Directions

The signaling cascade described in this review representsa molecular substrate underlying the mechanism by whichmicroglia target GABAergicglycinergic neurotransmissionHowever it is likely that BDNF released from microgliaalso challenge network excitability by mechanisms otherthan KCC2 In particular BDNF-TrkB signaling also targetsNMDA receptors [65 110] and microglial BDNF has beensuggested to underlie certain forms of pathological pain viathe activation of spinal NMDA [111] The outcome of bothKCC2 downregulation and NMDA potentiation is an overallincrease in network excitability This raises the question ofwhether modulations of KCC2 and NMDA functions areindependent processes or are reciprocally connected Severallines of evidence support the latter hypothesis [112 113] andfuture investigations are encouraged to further explore suchinteractions in different neurological disorders In addition toBDNFmicroglia are known to directly or indirectlymodulatesynaptic transmission through the release of tens of otherdifferentmolecules [114] Most of past studies have differentlyfocused on the effect of these molecules in the modulation ofglutamatergic transmission In this respect a role has beendescribed for cytokines [115] glycine [116] NMDA receptoragonists [117] adenosine [118] and ATP [119] On the otherhand a growing body of studies reported that cytokinesmight also directly modulate GABAergic transmission [115]interleukin 1120573 was found to depress GABA release in amodel of autoimmune encephalitis [120] and to potentiateGABAergic transmission in CA1 [121] or in hypothalamicneurons [122] both interleukin 6 and interleukin 1120573were seento reduce GABA- and Gly-mediated currents in the spinaldorsal horn [123] tumor necrosis factor 120572 was shown topromote GABAAR endocytosis in hippocampal neurons thusweakening the inhibitory synaptic strength [124] In additionmicroglia also produce lipophilic gaseous molecules such as

6 Neural Plasticity

minusminus

minus

KCC2Clminus

(a)

BDNF

minusminus

minus

KCC2Clminus

(b)

Figure 1Microglia control neuronal network excitability via secretion of BDNFThe left panel illustrates a schematic neuronal network in themature CNS under normal conditions microglia (blue ramified cells) are in their resting state small inhibitory interneurons release GABAor Gly to repress the flow of signals across the network normal KCC2 activity extrudes Clminus (black arrows) to maintain the Clminus gradient andconsequently Clminus flows in through GABAARGlyR channels to inhibit activity The right panel illustrates the same network after an externalevent has inducedmicroglial activation (red cells) and the release ofmicroglial BDNF BDNF-TrkB signaling causes downregulation of KCC2Clminus accumulates in neurons and the Clminus gradient collapses GABAARGlyR-mediated inhibition is less effective in controlling neuronal firingand previously silent neuronal pathways are unmasked (yellow arrows)

nitric oxide [125ndash127] and lipidic inflammatory mediatorssuch as prostaglandins [127 128] Interestingly prostaglandinE2 directly suppresses glycine-mediated transmission in thespinal dorsal horn a mechanism centrally involved in thedevelopment of inflammatory pain [129 130] Deeper insightsinto the role played by each of these messengers in normaland pathological conditions are required to improve ourunderstanding of the role of microglia-to-neuron communi-cation

Yet the effects reported in different studies for most ofthese microglia-derived molecules are often quite dissimilarand critically influenced by the experimental paradigmsdrug concentrations and neuronal populations considered[114] In addition the mechanisms leading to the releaseof specific molecules as well as the molecular pathwaysactivated in neurons are still poorly understood making itdifficult to draw a coherent picture for their role in synap-tic transmission Conversely the P2X4R-BDNF-TrkB-KCC2cascade described here appears to connect altered extracellu-lar conditionswithmicroglia activation neuronal excitabilityand eventually the development of a pathological behaviorCollectively these findings open new important therapeuticavenues for the control of neuropathic pain [25] and epilepsy[99] Yet many questions are left unanswered and need tobe addressed to better delineate the range of applicationsfor an effective microglia-targeted therapeutic strategy inparticular which neurological disorders are associated with amicroglia-driven loss of inhibition In which brain areas Doallmicroglia have the same potential to synthesize and release

BDNF when exposed to a given extracellular challengeOr instead are microglia a heterogeneous population withmultiple phenotypes playing different roles in different CNSareas and in different pathological states

Tackling the multiform universe of microglia-neuroninteractions and understanding the underlying molecularpathways offer the opportunity to identify specific biomarkersfor neurological disorders and potential targets for noveltherapeutic approaches

Acknowledgments

The authors are grateful to Mr Sylvain Cote for his preciousassistance in preparing the figure The authors acknowl-edge the financial support from the Canadian Institutesof Health Research the Natural Sciences and Engineer-ing Research Council of Canada the Fonds de rechercheQuebec-Sante the Krembil Foundation and the RegionePiemonteUniversity of Turin

References

[1] A Vezzani J French T Bartfai and T Z Baram ldquoThe role ofinflammation in epilepsyrdquo Nature Reviews Neurology vol 7 no1 pp 31ndash40 2011

[2] B Viviani F Gardoni and M Marinovich ldquoCytokines andneuronal ion channels in health and diseaserdquo InternationalReview of Neurobiology vol 82 pp 247ndash263 2007

Neural Plasticity 7

[3] B Viviani S Bartesaghi F Gardoni et al ldquoInterleukin-1120573 enhances NMDA receptor-mediated intracellular calciumincrease through activation of the Src family of kinasesrdquo Journalof Neuroscience vol 23 no 25 pp 8692ndash8700 2003

[4] H Fiumelli and M A Woodin ldquoRole of activity-dependentregulation of neuronal chloride homeostasis in developmentrdquoCurrent Opinion in Neurobiology vol 17 no 1 pp 81ndash86 2007

[5] A Harauzov M Spolidoro G DiCristo et al ldquoReducingintracortical inhibition in the adult visual cortex promotesocular dominance plasticityrdquo Journal of Neuroscience vol 30no 1 pp 361ndash371 2010

[6] D M Kullmann A W Moreau Y Bakiri and E NicholsonldquoPlasticity of inhibitionrdquo Neuron vol 75 no 6 pp 951ndash9622012

[7] C Labrakakis F Ferrini and Y de Koninck ldquoMechanisms ofplasticity of inhibition in chronic pain conditionsrdquo in InhibitorySynaptic Plasticity pp 91ndash105 Springer New York NY USA2011

[8] N Doyon S A Prescott A Castonguay A G Godin HKroger and Y de Koninck ldquoEfficacy of synaptic inhibitiondepends on multiple dynamically interacting mechanismsimplicated in chloride homeostasisrdquo PLoS Computational Biol-ogy vol 7 no 9 Article ID e1002149 2011

[9] S A Prescott T J Sejnowski and Y de Koninck ldquoReduction ofanion reversal potential subverts the inhibitory control of firingrate in spinal lamina I neurons towards a biophysical basis forneuropathic painrdquoMolecular Pain vol 2 article 32 2006

[10] Y de Koninck ldquoAltered chloride homeostasis in neurologicaldisorders a new targetrdquo Current Opinion in Pharmacology vol7 no 1 pp 93ndash99 2007

[11] P Blaesse M S Airaksinen C Rivera and K Kaila ldquoCation-chloride cotransporters and neuronal functionrdquoNeuron vol 61no 6 pp 820ndash838 2009

[12] T J Price F Cervero and Y de Koninck ldquoRole of cation-chloride-cotransporters (CCC) in pain and hyperalgesiardquo Cur-rent Topics in Medicinal Chemistry vol 5 no 6 pp 547ndash5552005

[13] J A Payne T J Stevenson and L F Donaldson ldquoMolecularcharacterization of a putative K-Cl cotransporter in rat brain aneuronal-specific isoformrdquo Journal of Biological Chemistry vol271 no 27 pp 16245ndash16252 1996

[14] C Rivera J Voipio J A Payne et al ldquoThe K+Cl- co-transporter KCC2 renders GABA hyperpolarizing during neu-ronal maturationrdquo Nature vol 397 no 6716 pp 251ndash255 1999

[15] M Cordero-Erausquin J A M Coull D Boudreau M Rol-land and Y de Koninck ldquoDifferential maturation of GABAaction and anion reversal potential in spinal lamina I neuronsimpact of chloride extrusion capacityrdquo Journal of Neurosciencevol 25 no 42 pp 9613ndash9623 2005

[16] C Rivera J Voipio and K Kaila ldquoTwo developmental switchesin GABAergic signalling the K+-Cl- cotransporter KCC2 andcarbonic anhydrase CAVIIrdquo Journal of Physiology vol 562 part1 pp 27ndash36 2005

[17] Y Ben-Ari J-L Gaiarsa R Tyzio and R Khazipov ldquoGABA apioneer transmitter that excites immature neurons and gener-ates primitive oscillationsrdquo Physiological Reviews vol 87 no 4pp 1215ndash1284 2007

[18] A Stil C Jean-Xavier S Liabeuf et al ldquoContribution of thepotassium-chloride co-transporter KCC2 to the modulation oflumbar spinal networks in micerdquo European Journal of Neuro-science vol 33 no 7 pp 1212ndash1222 2011

[19] J H Chancey EW Adlaf M C Sapp et al ldquoGABA depolariza-tion is required for experience-dependent synapse unsilencingin adult-born neuronsrdquo Journal of Neuroscience vol 33 no 15pp 6614ndash6622 2013

[20] S Ge D A Pradhan G-L Ming and H Song ldquoGABA setsthe tempo for activity-dependent adult neurogenesisrdquo Trends inNeurosciences vol 30 no 1 pp 1ndash8 2007

[21] P Boulenguez S Liabeuf R Bos et al ldquoDown-regulationof the potassium-chloride cotransporter KCC2 contributes tospasticity after spinal cord injuryrdquo Nature Medicine vol 16 no3 pp 302ndash307 2010

[22] S AHewitt J IWamsteeker EUKurz and J S Bains ldquoAlteredchloride homeostasis removes synaptic inhibitory constraint ofthe stress axisrdquo Nature Neuroscience vol 12 no 4 pp 438ndash4432009

[23] D Arion and D A Lewis ldquoAltered expression of regulatorsof the cortical chloride transporters NKCC1 and KCC2 inschizophreniardquo Archives of General Psychiatry vol 68 no 1 pp21ndash31 2011

[24] T M Hyde B K Lipska T Ali et al ldquoExpression of GABAsignaling molecules KCC2 NKCC1 and GAD1 in corticaldevelopment and schizophreniardquo Journal of Neuroscience vol31 no 30 pp 11088ndash11095 2011

[25] N Doyon F Ferrini M Gagnon and Y de Koninck ldquoTreatingpathological pain is KCC2 the key to the gaterdquo Expert Reviewof Neurotherapeutics vol 13 no 5 pp 469ndash471 2013

[26] G Huberfeld LWittner S Clemenceau et al ldquoPerturbed chlo-ride homeostasis and GABAergic signaling in human temporallobe epilepsyrdquo Journal of Neuroscience vol 27 no 37 pp 9866ndash9873 2007

[27] J A M Coull S Beggs D Boudreau et al ldquoBDNF frommicroglia causes the shift in neuronal anion gradient underlyingneuropathic painrdquo Nature vol 438 no 7070 pp 1017ndash10212005

[28] F Ferrini T Trang T A Mattioli et al ldquoMorphine hyperalgesiagated through microglia-mediated disruption of neuronal Clminushomeostasisrdquo Nature Neuroscience vol 16 no 2 pp 183ndash1922013

[29] C Rivera H Li JThomas-Crusells et al ldquoBDNF-induced TrkBactivation down-regulates the K+-Cl- cotransporter KCC2 andimpairs neuronal Cl- extrusionrdquo Journal of Cell Biology vol 159no 5 pp 747ndash752 2002

[30] C Rivera J Voipio J Thomas-Crusells et al ldquoMechanism ofactivity-dependent downregulation of the neuron-specific K-Clcotransporter KCC2rdquo Journal of Neuroscience vol 24 no 19 pp4683ndash4691 2004

[31] W Zhang L-Y Liu andT-L Xu ldquoReduced potassium-chlorideco-transporter expression in spinal cord dorsal horn neuronscontributes to inflammatory pain hypersensitivity in ratsrdquoNeuroscience vol 152 no 2 pp 502ndash510 2008

[32] T Trang S Beggs and M W Salter ldquoBrain-derived neu-rotrophic factor from microglia a molecular substrate forneuropathic painrdquoNeuron Glia Biology vol 7 no 1 pp 99ndash1082011

[33] M PMattson ldquoGlutamate and neurotrophic factors in neuronalplasticity and diseaserdquo Annals of the New York Academy ofSciences vol 1144 pp 97ndash112 2008

[34] A Merighi C Salio A Ghirri et al ldquoBDNF as a painmodulatorrdquo Progress in Neurobiology vol 85 no 3 pp 297ndash3172008

8 Neural Plasticity

[35] A R Santos D Comprido and C B Duarte ldquoRegulation oflocal translation at the synapse by BDNFrdquo Progress in Neurobi-ology vol 92 no 4 pp 505ndash516 2010

[36] A Figurov L D Pozzo-Miller P Olafsson T Wang and B LuldquoRegulation of synaptic responses to high-frequency stimula-tion and LTP by neurotrophins in the hippocampusrdquo Naturevol 381 no 6584 pp 706ndash709 1996

[37] SMartyM Da and B Berninger ldquoNeurotrophins and activity-dependent plasticity of cortical interneuronsrdquo Trends in Neuro-sciences vol 20 no 5 pp 198ndash202 1997

[38] A L Mahan and K J Ressler ldquoFear conditioning synapticplasticity and the amygdala implications for posttraumaticstress disorderrdquo Trends in Neurosciences vol 35 no 1 pp 24ndash35 2012

[39] Y Huang J J Wang and W H Yung ldquoCoupling betweenGABA-A receptor and chloride transporter underlies ionicplasticity in cerebellar purkinje neuronsrdquo Cerebellum vol 12no 3 pp 328ndash330 2013

[40] K Gottmann TMittmann and V Lessmann ldquoBDNF signalingin the formationmaturation and plasticity of glutamatergic andGABAergic synapsesrdquoExperimental Brain Research vol 199 no3-4 pp 203ndash234 2009

[41] N H Woo and B Lu ldquoBDNF in synaptic plasticity andmemoryrdquo in Intercellular Communication in theNervous SystemMalenka Rpp pp 590ndash598 Academic Press London UK 2009

[42] M Frerking R C Malenka and R A Nicoll ldquoBrain-derivedneurotrophic factor (BDNF) modulates inhibitory but notexcitatory transmission in the CA1 region of the hippocampusrdquoJournal of Neurophysiology vol 80 no 6 pp 3383ndash3386 1998

[43] T Tanaka H Saito and N Matsuki ldquoInhibition of GABA(A)synaptic responses by brain-derived neurotrophic factor(BDNF) in rat hippocampusrdquo Journal of Neuroscience vol 17no 9 pp 2959ndash2966 1997

[44] P Baldelli M Novara V Carabelli J M Hernandez-Guijo andE Carbone ldquoBDNF up-regulates evoked GABAergic transmis-sion in developing hippocampus by potentiating presynaptic N-and PQ-type Ca2+ channels signallingrdquo European Journal ofNeuroscience vol 16 no 12 pp 2297ndash2310 2002

[45] P Baldelli J-MHernandez-Guijo V Carabelli andECarboneldquoBrain-derived neurotrophic factor enhances GABA releaseprobability and nonuniform distribution of N- and PQ-typechannels on release sites of hippocampal inhibitory synapsesrdquoJournal of Neuroscience vol 25 no 13 pp 3358ndash3368 2005

[46] Y Mizoguchi H Ishibashi and J Nabekura ldquoThe action ofBDNF on GABAA currents changes from potentiating to sup-pressing during maturation of rat hippocampal CA1 pyramidalneuronsrdquo Journal of Physiology vol 548 part 3 pp 703ndash7092003

[47] E A Ivakine B A Acton V Mahadevan et al ldquoNeto2 is aKCC2 interacting protein required for neuronal Cl-regulationin hippocampal neuronsrdquo Proceedings of the National Academyof Sciences of the United States of America vol 110 no 9 pp3561ndash3566 2013

[48] H Wake M Watanabe A J Moorhouse et al ldquoEarly changesin KCC2 phosphorylation in response to neuronal stress resultin functional downregulationrdquo Journal of Neuroscience vol 27no 7 pp 1642ndash1650 2007

[49] P Blaesse I Guillemin J Schindler et al ldquoOligomerization ofKCC2 correlates with development of inhibitory neurotrans-missionrdquo Journal of Neuroscience vol 26 no 41 pp 10407ndash10419 2006

[50] M Watanabe H Wake A J Moorhouse and J NabekuraldquoClustering of neuronal K+-Cl- cotransporters in lipid rafts bytyrosine phosphorylationrdquo Journal of Biological Chemistry vol284 no 41 pp 27980ndash27988 2009

[51] S Zadran H Jourdi K Rostamiani G Qin X Bi andM Baudry ldquoBrain-derived neurotrophic factor and epider-mal growth factor activate neuronal m-calpain via mitogen-activated protein kinase-dependent phosphorylationrdquo Journalof Neuroscience vol 30 no 3 pp 1086ndash1095 2010

[52] H Vargas-Perez R T-A Kee C H Walton et al ldquoVentraltegmental area BDNF induces an opiate-dependent-like rewardstate in naıve ratsrdquo Science vol 324 no 5935 pp 1732ndash17342009

[53] M Fukuchi T Nii N Ishimaru et al ldquoValproic acid inducesup- or down-regulation of gene expression responsible forthe neuronal excitation and inhibition in rat cortical neuronsthrough its epigenetic actionsrdquo Neuroscience Research vol 65no 1 pp 35ndash43 2009

[54] GMolinaroG Battaglia B Riozzi et al ldquoMemantine treatmentreduces the expression of the K+Cl- cotransporter KCC2 in thehippocampus and cerebral cortex and attenuates behaviouralresponses mediated by GABAA receptor activation in micerdquoBrain Research vol 1265 pp 75ndash79 2009

[55] S Pezet M Malcangio and S B McMahon ldquoBDNF a neuro-modulator in nociceptive pathwaysrdquo Brain Research Reviewsvol 40 no 1ndash3 pp 240ndash249 2002

[56] V Parpura and R Zorec ldquoGliotransmission exocytotic releasefrom astrocytesrdquoBrain Research Reviews vol 63 no 1-2 pp 83ndash92 2010

[57] S Elkabes E M DiCicco-Bloom and I B Black ldquoBrainmicrogliamacrophages express neurotrophins that selectivelyregulate microglial proliferation and functionrdquo Journal of Neu-roscience vol 16 no 8 pp 2508ndash2521 1996

[58] T Miwa S Furukawa K Nakajima et al ldquoLipopolysaccharideenhances synthesis of brain-derived neurotrophic factor incultured ratmicrogliardquo Journal ofNeuroscience Research vol 50no 6 pp 1023ndash1029 1997

[59] V Soontornniyomkij G Wang C A Pittman C A Wileyand C L Achim ldquoExpression of brain-derived neurotrophicfactor protein in activated microglia of human immunodefi-ciency virus type 1 encephalitisrdquo Neuropathology and AppliedNeurobiology vol 24 no 6 pp 453ndash460 1998

[60] P E Batchelor G T Liberatore J Y F Wong et al ldquoActivatedmacrophages and microglia induce dopaminergic sprouting inthe injured striatum and express brain-derived neurotrophicfactor and glial cell line-derived neurotrophic factorrdquo Journalof Neuroscience vol 19 no 5 pp 1708ndash1716 1999

[61] K D Dougherty C F Dreyfus and I B Black ldquoBrain-derived neurotrophic factor in astrocytes oligodendrocytesand microgliamacrophages after spinal cord injuryrdquo Neurobi-ology of Disease vol 7 no 6 pp 574ndash585 2000

[62] T-H Lee H Kato S-T Chen K Kogure and Y ItoyamaldquoExpression disparity of brain-derived neurotrophic factorimmunoreactivity and mRNA in ischemic hippocampal neu-ronsrdquo NeuroReport vol 13 no 17 pp 2271ndash2275 2002

[63] C Stadelmann M Kerschensteiner T Misgeld W Bruck RHohlfeld and H Lassmann ldquoBDNF and gp145trkB in multiplesclerosis brain lesions neuroprotective interactions betweenimmune and neuronal cellsrdquo Brain vol 125 part 1 pp 75ndash852002

[64] C Knott G Stern A Kingsbury A A Welcher and G PWilkin ldquoElevated glial brain-derived neurotrophic factor in

Neural Plasticity 9

Parkinsonrsquos diseased nigrardquo Parkinsonism and Related Disor-ders vol 8 no 5 pp 329ndash341 2002

[65] L Ulmann J P Hatcher J P Hughes et al ldquoUp-regulationof P2X4 receptors in spinal microglia after peripheral nerveinjury mediates BDNF release and neuropathic painrdquo Journalof Neuroscience vol 28 no 44 pp 11263ndash11268 2008

[66] S Beggs T Trang and M W Salter ldquoP2X4R+ microglia driveneuropathic painrdquoNature Neuroscience vol 15 no 8 pp 1068ndash1073 2012

[67] T Trang S Beggs X Wan and M W Salter ldquoP2X4-receptor-mediated synthesis and release of brain-derived neurotrophicfactor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activationrdquo Journal of Neuroscience vol29 no 11 pp 3518ndash3528 2009

[68] K Inoue ldquoMicroglial activation by purines and pyrimidinesrdquoGlia vol 40 no 2 pp 156ndash163 2002

[69] Y Pankratov U Lalo A Verkhratsky and R A North ldquoVesicu-lar release of ATP at central synapsesrdquo Pflugers Archiv EuropeanJournal of Physiology vol 452 no 5 pp 589ndash597 2006

[70] P B Guthrie J KnappenbergerM SegalM V L Bennett A CCharles and S B Kater ldquoATP released from astrocytesmediatesglial calcium wavesrdquo Journal of Neuroscience vol 19 no 2 pp520ndash528 1999

[71] S E Haynes G Hollopeter G Yang et al ldquoThe P2Y12 receptorregulates microglial activation by extracellular nucleotidesrdquoNature Neuroscience vol 9 no 12 pp 1512ndash1519 2006

[72] K Ohsawa Y Irino Y Nakamura C Akazawa K Inoue andS Kohsaka ldquoInvolvement of P2X4 and P2Y12 receptors in ATP-inducedmicroglial chemotaxisrdquoGlia vol 55 no 6 pp 604ndash6162007

[73] M Monif C A Reid K L Powell M L Smart and DA Williams ldquoThe P2X7 receptor drives microglial activationand proliferation a trophic role for P2X7R porerdquo Journal ofNeuroscience vol 29 no 12 pp 3781ndash3791 2009

[74] K Biber M Tsuda H Tozaki-Saitoh et al ldquoNeuronal CCL21up-regulates microglia P2X4 expression and initiates neuro-pathic pain developmentrdquoThe EMBO Journal vol 30 no 9 pp1864ndash1873 2011

[75] E Toyomitsu M Tsuda T Yamashita H Tozaki-Saitoh YTanaka and K Inoue ldquoCCL2 promotes P2X4 receptor traffick-ing to the cell surface of microgliardquo Purinergic Signalling vol 8no 2 pp 301ndash310 2012

[76] C Abbadie J A Lindia A M Cumiskey et al ldquoImpairedneuropathic pain responses in mice lacking the chemokinereceptor CCR2rdquo Proceedings of the National Academy of Sciencesof the United States of America vol 100 no 13 pp 7947ndash79522003

[77] J Zhang Q S Xiang S Echeverry J S Mogil Y de Koninckand S Rivest ldquoExpression of CCR2 in both resident and bonemarrow-derived microglia plays a critical role in neuropathicpainrdquo Journal of Neuroscience vol 27 no 45 pp 12396ndash124062007

[78] M Tsuda T Masuda J Kitano H Shimoyama H Tozaki-Saitoh and K Inoue ldquoIFN-120574 receptor signaling mediates spinalmicroglia activation driving neuropathic painrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 106 no 19 pp 8032ndash8037 2009

[79] H Yuan X Zhu S Zhou et al ldquoRole of mast cell activationin inducing microglial cells to release neurotrophinrdquo Journal ofNeuroscience Research vol 88 no 6 pp 1348ndash1354 2010

[80] K Nasu-Tada S Koizumi M Tsuda E Kunifusa and K InoueldquoPossible involvement of increase in spinal fibronectin follow-ing peripheral nerve injury in upregulation of microglial P2X4a key molecule for mechanical allodyniardquoGlia vol 53 no 7 pp769ndash775 2006

[81] MTsuda E Toyomitsu T Komatsu et al ldquoFibronectinintegrinsystem is involved in P2X4 receptor upregulation in the spinalcord and neuropathic pain after nerve injuryrdquo Glia vol 56 no5 pp 579ndash585 2008

[82] T Masuda M Tsuda R Yoshinaga et al ldquoIRF8 is a criticaltranscription factor for transforming microglia into a reactivephenotyperdquo Cell Reports vol 1 no 4 pp 334ndash340 2012

[83] J Miao M Ding A Zhang et al ldquoPleiotrophin promotesmicroglia proliferation and secretion of neurotrophic factorsby activating extracellular signal-regulated kinase 12 pathwayrdquoNeuroscience Research vol 74 no 3-4 pp 269ndash276 2012

[84] N Takayama and H Ueda ldquoMorphine-induced chemotaxisand brain-derived neurotrophic factor expression inmicrogliardquoJournal of Neuroscience vol 25 no 2 pp 430ndash435 2005

[85] R Bardoni T Takazawa C K Tong et al ldquoPre- and postsynap-tic inhibitory control in the spinal cord dorsal hornrdquo Annals ofthe New York Academy of Sciences vol 1279 pp 90ndash96 2013

[86] L A Roberts C Beyer and B R Komisaruk ldquoNociceptiveresponses to altered GABAergic activity at the spinal cordrdquo LifeSciences vol 39 no 18 pp 1667ndash1674 1986

[87] T L Yaksh ldquoBehavioral and autonomic correlates of the tactileevoked allodynia produced by spinal glycine inhibition effectsof modulatory receptor systems and excitatory amino acidantagonistsrdquo Pain vol 37 no 1 pp 111ndash123 1989

[88] J A M Coull D Boudreau K Bachand et al ldquoTrans-synaptic shift in anion gradient in spinal lamina I neurons asa mechanism of neuropathic painrdquo Nature vol 424 no 6951pp 938ndash942 2003

[89] H Aldskogius ldquoRegulation of microgliamdashpotential new drugtargets in the CNSrdquo Expert Opinion onTherapeutic Targets vol5 no 6 pp 655ndash668 2001

[90] J L Arruda S Sweitzer M D Rutkowski and J A DeleoldquoIntrathecal anti-IL-6 antibody and IgG attenuates peripheralnerve injury-induced mechanical allodynia in the rat possibleimmune modulation in neuropathic painrdquo Brain Research vol879 no 1-2 pp 216ndash225 2000

[91] S-X Jin Z-Y Zhuang C J Woolf and R-R Ji ldquop38 mitogen-activated protein kinase is activated after a spinal nerve ligationin spinal cord microglia and dorsal root ganglion neurons andcontributes to the generation of neuropathic painrdquo Journal ofNeuroscience vol 23 no 10 pp 4017ndash4022 2003

[92] M Tsuda Y Shigemoto-Mogami S Koizumi et al ldquoP2X4receptors induced in spinal microglia gate tactile allodynia afternerve injuryrdquo Nature vol 424 no 6950 pp 778ndash783 2003

[93] Y Lu J Zheng L Xiong M Zimmermann and J Yang ldquoSpinalcord injury-induced attenuation of GABAergic inhibition inspinal dorsal horn circuits is associated with down-regulationof the chloride transporter KCC2 in ratrdquo Journal of Physiologyvol 586 part 23 pp 5701ndash5715 2008

[94] C G Jolivalt C A Lee K M Ramos and N A Calcutt ldquoAllo-dynia and hyperalgesia in diabetic rats are mediated by GABAand depletion of spinal potassium-chloride co-transportersrdquoPain vol 140 no 1 pp 48ndash57 2008

[95] B Wei T Kumada T Furukawa et al ldquoPre- and post-synapticswitches of GABA actions associated with Cl- homeostaticchanges are induced in the spinal nucleus of the trigeminal

10 Neural Plasticity

nerve in a rat model of trigeminal neuropathic painrdquo Neuro-science vol 228 pp 334ndash348 2013

[96] S Malhotra A D Pandyan C R Day P W Jones and HHermens ldquoSpasticity an impairment that is poorly defined andpoorly measuredrdquo Clinical Rehabilitation vol 23 no 7 pp 651ndash658 2009

[97] B C Hains and S G Waxman ldquoActivated microglia contributeto the maintenance of chronic pain after spinal cord injuryrdquoJournal of Neuroscience vol 26 no 16 pp 4308ndash4317 2006

[98] W H Lu C Y Wang P S Chen et al ldquoValproic acidattenuates microgliosis in injured spinal cord and purinergicP2X4 receptor expression in activated microgliardquo Journal ofNeuroscience Research vol 91 no 5 pp 694ndash705 2013

[99] R Miles P Blaesse G Huberfeld et al ldquoChloride homeostasisand GABA signaling in temporal lobe epilepsyrdquo in Jasperrsquos BasicMechanisms of the Epilepsies [Internet] J L Noebeles M AvoliM A Rogawski R W Olsen and A V Delgado-Escueta EdsNational Center for Biotechnology Information (US) BethesdaMd USA 4th edition 2012

[100] C Bernard ldquoAlterations in synaptic function in epilepsyrdquo inJasperrsquos Basic Mechanisms of the Epilepsies [Internet] J LNoebeles M Avoli M A Rogawski R W Olsen and AV Delgado-Escueta Eds National Center for BiotechnologyInformation (US) Bethesda Md USA 4th edition 2012

[101] A Shulga J Thomas-Crusells T Sigl et al ldquoPosttraumaticGABAA-mediated [Ca2+]i increase is essential for the induc-tion of brain-derived neurotrophic factor-dependent survival ofmature central neuronsrdquo Journal of Neuroscience vol 28 no 27pp 6996ndash7005 2008

[102] A Vezzani E Aronica AMazarati andQ J Pittman ldquoEpilepsyand brain inflammationrdquo Experimental Neurology vol 244 pp11ndash21 2013

[103] A D Bachstetter R K Rowe M Kaneko et al ldquoThe p38alphaMAPK regulates microglial responsiveness to diffuse traumaticbrain injuryrdquo Journal of Neuroscience vol 33 no 14 pp 6143ndash6153 2013

[104] Z ZhangM ArteltM Burnet K Trautmann andH J Schlue-sener ldquoLesional accumulation of P2X4 receptor+ monocytesfollowing experimental traumatic brain injuryrdquo ExperimentalNeurology vol 197 no 1 pp 252ndash257 2006

[105] J M Schwarz and S D Bilbo ldquoAdolescent morphine exposureaffects long-term microglial function and later-life relapseliability in a model of addictionrdquo Journal of Neuroscience vol33 no 3 pp 961ndash971 2013

[106] A Ludwig P Uvarov S Soni JThomas-Crusells M S Airaksi-nen and C Rivera ldquoEarly growth response 4 mediates BDNFinduction of potassium chloride cotransporter 2 transcriptionrdquoJournal of Neuroscience vol 31 no 2 pp 644ndash649 2011

[107] R H Lipsky and A M Marini ldquoBrain-derived neurotrophicfactor in neuronal survival and behavior-related plasticityrdquoAnnals of the New York Academy of Sciences vol 1122 pp 130ndash143 2007

[108] A Aguzzi B A Barres and M L Bennett ldquoMicroglia scape-goat saboteur or something elserdquo Science vol 339 no 6116 pp156ndash161 2013

[109] A F Keller S Beggs M W Salter and Y de KoninckldquoTransformation of the output of spinal lamina I neurons afternerve injury and microglia stimulation underlying neuropathicpainrdquoMolecular Pain vol 3 article 27 2007

[110] R A Crozier C Bi Y R Han and M R Plummer ldquoBDNFmodulation of NMDA receptors is activity dependentrdquo Journalof Neurophysiology vol 100 no 6 pp 3264ndash3274 2008

[111] L-N Wang J-P Yang F-H Ji et al ldquoBrain-derived neu-rotrophic factor modulates N-methyl-D-aspartate receptoractivation in a rat model of cancer-induced bone painrdquo Journalof Neuroscience Research vol 90 no 6 pp 1249ndash1260 2012

[112] H H C Lee T Z Deeb J A Walker P A Davies and S JMoss ldquoNMDA receptor activity downregulates KCC2 resultingin depolarizing GABAA receptor-mediated currentsrdquo NatureNeuroscience vol 14 no 6 pp 736ndash743 2011

[113] M Puskarjov F Ahmad K Kaila and P Blaesse ldquoActivity-dependent cleavage of the K-Cl cotransporter KCC2 mediatedby calcium-activated protease calpainrdquo Journal of Neurosciencevol 32 no 33 pp 11356ndash11364 2012

[114] C Bechade Y Cantaut-Belarif and A Bessis ldquoMicroglialcontrol of neuronal activityrdquo Frontiers in Cellular Neurosciencevol 7 article 32 2013

[115] M A Galic K Riazi and Q J Pittman ldquoCytokines and brainexcitabilityrdquo Frontiers in Neuroendocrinology vol 33 no 1 pp116ndash125 2012

[116] Y Hayashi H Ishibashi K Hashimoto and H Nakan-ishi ldquoPotentiation of the NMDA receptor-mediated responsesthrough the activation of the glycine site by microglia secretingsoluble factorsrdquo Glia vol 53 no 6 pp 660ndash668 2006

[117] J Steiner M Walter T Gos et al ldquoSevere depression is asso-ciated with increased microglial quinolinic acid in subregionsof the anterior cingulate gyrus evidence for an immune-modulated glutamatergic neurotransmissionrdquo Journal of Neu-roinflammation vol 8 article 94 2011

[118] S Piccinin S di Angelantonio A Piccioni et al ldquoCX3CL1-induced modulation at CA1 synapses reveals multiple mech-anisms of EPSC modulation involving adenosine receptorsubtypesrdquo Journal of Neuroimmunology vol 224 no 1-2 pp 85ndash92 2010

[119] O Pascual S B Achour P Rostaing A Triller and A BessisldquoMicroglia activation triggers astrocyte-mediated modulationof excitatory neurotransmissionrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 109 no4 pp E197ndashE205 2012

[120] G Mandolesi G Grasselli A Musella et al ldquoGABAergicsignaling and connectivity on Purkinje cells are impaired inexperimental autoimmune encephalomyelitisrdquo Neurobiology ofDisease vol 46 no 2 pp 414ndash424 2012

[121] F P Bellinger S Madamba and G R Siggins ldquoInterleukin 1120573inhibits synaptic strength and long-term potentiation in the ratCA1 hippocampusrdquo Brain Research vol 628 no 1-2 pp 227ndash234 1993

[122] I V Tabarean H Korn and T Bartfai ldquoInterleukin-1120573 induceshyperpolarization and modulates synaptic inhibition in preop-tic and anterior hypothalamic neuronsrdquo Neuroscience vol 141no 4 pp 1685ndash1695 2006

[123] Y Kawasaki L Zhang J-K Cheng and R-R Ji ldquoCytokinemechanisms of central sensitization distinct and overlappingrole of interleukin-1120573 interleukin-6 and tumor necrosis factor-120572 in regulating synaptic and neuronal activity in the superficialspinal cordrdquo Journal of Neuroscience vol 28 no 20 pp 5189ndash5194 2008

[124] D Stellwagen E C Beattie J Y Seo and R C MalenkaldquoDifferential regulation of AMPA receptor and GABA receptortrafficking by tumor necrosis factor-120572rdquo Journal of Neurosciencevol 25 no 12 pp 3219ndash3228 2005

[125] N R Bhat P Zhang J C Lee and E L Hogan ldquoExtracellularsignal-regulated kinase and p38 subgroups of mitogen- acti-vated protein kinases regulate inducible nitric oxide synthase

Neural Plasticity 11

and tumor necrosis factor-120572 gene expression in endotoxin-stimulated primary glial culturesrdquo Journal of Neuroscience vol18 no 5 pp 1633ndash1641 1998

[126] E Galea D L Feinstein and D J Reis ldquoInduction of calcium-independent nitric oxide synthase activity in primary rat glialculturesrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 89 no 22 pp 10945ndash10949 1992

[127] T Matsui C I Svensson Y Hirata K Mizobata X-Y Hua andT L Yaksh ldquoRelease of prostaglandin E2 and nitric oxide fromspinal microglia is dependent on activation of p38 mitogen-activated protein kinaserdquo Anesthesia and Analgesia vol 111 no2 pp 554ndash560 2010

[128] O Saito C I Svensson M W Buczynski et al ldquoSpinal glialTLR4-mediated nociception and production of prostaglandinE2 and TNFrdquo British Journal of Pharmacology vol 160 no 7pp 1754ndash1764 2010

[129] S Ahmadi S Lippross W L Neuhuber and H U ZeilhoferldquoPGE2 selectively blocks inhibitory glycinergic neurotransmis-sion onto rat superficial dorsal horn neuronsrdquo Nature Neuro-science vol 5 no 1 pp 34ndash40 2002

[130] R J Harvey U B Depner H Wassle et al ldquoGlyR 1205723 anessential target for spinal PGE2-mediated inflammatory painsensitizationrdquo Science vol 304 no 5672 pp 884ndash887 2004

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


BioMed Research International


Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


Neural Plasticity


Parkinsonrsquos Disease


Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Psychiatry Journal


Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases


Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

2 Neural Plasticity

neurons is set below the resting potential (Vr) near the Clminusequilibrium (ECl) It follows that when GABAARGlyR areactivated Clminus produces a net hyperpolarization Although inprinciple correct this brief summary of the ionicmechanismsof synaptic inhibition provides a quite static representation ofGABAGly-mediated transmission and importantly does nottake into account that EGABAEGly and Vr being only fewmillivolts apart even a small change in anion concentrationsmay have a profound functional impact [8 9] In this respectthe critical variable is represented by the intracellular Clminusconcentration and the critical property is the capacity ofthe cell to maintain this concentration low In the eventthat intracellular Clminus rises it follows that (i) EGABAEGlyshifts toward or beyond Vr (ii) the Clminus gradient acrossthe membrane collapses and (iii) the previously negligibledepolarizing HCO

3

minus current becomes more relevant Onthe whole an increase in the intracellular Clminus concentrationweakens the strength of GABAGly-mediated inhibition orin the extreme case turns it into paradoxical excitation [10]

How do neurons control intracellular Clminus concentrationChloride homeostasis in cells is maintained by a group ofmembrane carriers known as cation-chloride cotransporters(CCCs [11 12]) The K+-Clminus cotransporter 2 KCC2 is themain CCC isoform expressed in central neurons [13 14]KCC2 extrudes Clminus following the K+ gradient and its activitytypically maintains a low intracellular Clminus concentrationwhich is the prerequisite for an effectiveGABAGly-mediatedinhibition Now KCC2 activity is not static but it can be pro-foundly modulated by different physiological or pathologicalchallenges The most spectacular example of such plasticityhas been extensively described during development [14ndash16] KCC2 is little expressed in prenatal and early postnatalbrains but during maturation it undergoes a developmentalincrease which parallels the switch in GABAGly-mediatedtransmission from excitatory to inhibitory [14] These mech-anisms are thought not only to play a pivotal role in theactivity-dependent development of central synapses duringCNS maturation [17] but also to favor a proper wiring bytriggering spontaneous rhythmic activity in motor networks[18] and to promote synaptic integration of new born neuronsin those area of the brain in which adult neurogenesis occurs[19 20] On the other hand reduction of KCC2 activityhas been associated with several neurological diseases andconditions originally epilepsy and neuropathic pain [10]and more recently motor spasticity [21] stress [22] andschizophrenia [23 24] Several lines of evidence accumulatedduring the last decade have indeed demonstrated that theincrease in excitability in these pathological conditions canbe largely explained by a loss of inhibition and KCC2 hasbeen recognized as a keymolecular target underlying this loss[25 26]

The findings in recent years that KCC2 can be dynam-ically modulated by several intercellular signaling pathwayshave been particularly interesting [4] the most prevalentbeing brain-derived neurotrophic factor (BDNF) signalingonto neuronal TrkB receptors [27ndash31] Even more intriguingis the finding that in certain conditions BDNF in the CNS isnot only released by neurons but also bymicroglia [32] In thisreview we summarize and discuss the more relevant findings

supporting the role of microglia in conditioning KCC2 func-tion as well as consequently inhibitory neurotransmissionthrough the release of BDNF Several convergent findingsuncover a canonical signaling mechanism by which theimmune system can control neuronal network excitability byregulating the strength of inhibition

2 Role of BDNF in the Control ofKCC2 Function

BDNF is a neurotrophin with important functions in neu-ronal survival and differentiation However beyond its clas-sical neurotrophic role BDNF is directly involved in thecontrol of neuronal activity and synaptic plasticity as a neuro-modulator [33ndash35] These functions are described in severalareas of the CNS such as hippocampus [36] cortex [37]amygdala [38] cerebellum [39] and spinal cord [34] and areinvolved in different forms of plasticity [40 41] Althoughinitial studies mainly focused on glutamatergic synapsesthe effects of BDNF on GABAergic transmission have latelyreceived increasing attention [40] Interestingly early workon these effects performed in the rat hippocampus yieldeda number of conflicting results unveiling a more complexpicture than expected Indeed in juvenile rodents BDNFwas found to favor a substantial depression of GABAergictransmission via either pre- or postsynaptic mechanisms[42 43] conversely studies in immature neurons showedan overall potentiating effect [44 45] To explain such adiscrepancy it was hypothesized that the effect of BDNF ontoGABAergic transmission in hippocampal neurons might bedevelopmentally regulated in parallel with the switch inGABAergic transmission from excitatory to inhibitory [46]Thus BDNF depresses GABAergic transmission in matureneuronswhenGABA is inhibitory andpotentiates it in imma-ture neurons when GABA is depolarizing favoring activity-dependent synapse formation which has been relayed toGABA-mediated Ca2+ entry in developing neurons [37 4446] The fact that the changes in BDNF effects on GABA-mediated transmission are coincident with the developmen-tal switch in GABAergic current polarity raised the questionof whether BDNF has an effect on KCC2 function andorexpression This was indeed demonstrated by Rivera andcolleagues [29 30] The authors provided evidence thatin hippocampal slices BDNF rapidly downregulates KCC2expression through the BDNF preferred receptor TrkB (tyro-sine kinase B receptor) thus reducing neuronal Clminus extrusioncapacity [29]The effect required the activation of two down-stream cascades involving src homology 2 domain containingtransforming proteinFGF receptor substrate 2 (ShcFRS-2)and phospholipase C 120574- (PLC120574-) cAMP response element-binding protein signaling respectively [30] Interestinglythe activation of the Shc pathway alone was surprisinglyfound to promote the upregulation of KCC2 which mightelegantly explain the opposite effects of BDNF across braindevelopment based on the specific intracellular pathwaysinvolved [30] One important point of this study is that themembrane level of KCC2 undergoes a fast turnover rate andthis turnover is accelerated by exogenous BDNF or by an

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Neural Plasticity 7

































8 Neural Plasticity































Neural Plasticity 9




















































































Neural Plasticity










Psychiatry Journal









Journal of


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6 Future Directions


6 Neural Plasticity

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Acknowledgments


References



Neural Plasticity 7

































8 Neural Plasticity































Neural Plasticity 9




















































































Neural Plasticity










Psychiatry Journal









Journal of


6 Neural Plasticity

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Acknowledgments


References



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8 Neural Plasticity































Neural Plasticity 9




















































































Neural Plasticity










Psychiatry Journal









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8 Neural Plasticity































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