NF-kB in the Nervous Systemcshperspectives.cshlp.org/content/1/3/a001271.full.pdf · peripheral nerves are part of the PNS. The CNS coordinates different tasks: integration of all

NF-kB in the Nervous System

Barbara Kaltschmidt1 and Christian Kaltschmidt2

1Molecular Neurobiology, University of Bielefeld, Universitatsstr. 25, D-33501 Bielefeld2Cell Biology, University of Bielefeld, Universitatsstr. 25, D-33501 Bielefeld

Correspondence: [email protected]

The transcription factor NF-kB has diverse functions in the nervous system, depending on thecellular context. NF-kB is constitutively activated in glutamatergic neurons. Knockout of p65or inhibition of neuronal NF-kB by super-repressor IkB resulted in the loss of neuroprotectionand defects in learning and memory. Similarly, p502/2 mice have a lower learning abilityand are sensitive to neurotoxins. Activated NF-kB can be transported retrogradely fromactivated synapses to the nucleus to translate short-term processes to long-term changessuch as axon growth, which is important for long-term memory. In glia, NF-kB is inducibleand regulates inflammatory processes that exacerbate diseases such as autoimmune ence-phalomyelitis, ischemia, and Alzheimer’s disease. In summary, inhibition of NF-kB in gliamight ameliorate disease, whereas activation in neurons might enhance memory. Thisreview focuses on results produced by the analysis of genetic models.

In vertebrates, the nervous system is composedof the central nervous system (CNS) and the

peripheral nervous system (PNS). The CNScomprises the brain and spinal cord, whereasperipheral nerves are part of the PNS. TheCNS coordinates different tasks: integration ofall stimuli that are presented from outside orinside the organism, coordination of all motorprocesses, regulation of hormone systems, andorgan control. The most fascinating functionof the brain is the coordination of learningand memory. This review will focus on the func-tion of NF-kB in the nervous system, especiallyin learning and memory in rodent geneticmodels. The most abundant cell types in thevertebrate nervous system are neurons (about100 billion) and glia (10–50 times more).

Typical glial cells are astrocytes, microglia,and the nerve fiber ensheathing cells, such asSchwann cells, which insulate nerves in the PNSand oligodendrocytes in the CNS. Neurons arehighly polarized cells. Dendrites and/or somareceive electrochemical signals that are trans-mitted by axons to other neurons. Synapses aremajor sites of information input or output.These are formed by the presynaptic boutonsderived from axons and the postsynaptic sitesmainly localized on dendrites.

In a short introduction to the neurobiologyof learning, we present a reductionist view(Dudai 1989). Although it is not easy to for-mally define learning (see Dudai 1989), herelearning is defined simply as the capability ofan animal to acquire novel skills. Learning can

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lead to a lasting modification of the internalrepresentations of the outer world. Memoryis thus the retention of the outer worldexperience-dependent internal representations.Memory retrieval is the use of memory in be-havioral tasks. Comparison of learning capa-bilities in different species has suggested thatlearning has developed to provide organismswith an improved coping mechanism againstadverse environments. Thus the ability tolearn is encoded within the genome.

Over the years, a biochemical/cellularconcept of memory has emerged that can besummarized as a dialogue between genes andsynapses (Kandel 2001). Central to thisconcept is synaptic transmission, which is therelease of, for example, excitatory neurotrans-mitters (axon potential-inducing) from a pre-synaptic release site. Transformation of anaxon potential to neurotransmitter releasetakes place at presynaptic sites and is a uni-directional process. Two major transmittersystems in the CNS are predominant: gluta-mate, released from excitatory glutamatergicneurons, and g-aminobutyric acid (GABA),released from inhibitory GABAergic neurons.Glutamate can direct the opening of Naþ ionchannels at the postsynaptic site, inducing anexcitatory neuronal response. In contrast,GABA directs the opening of Cl2 channels,thus inducing an inhibitory response.Activity-dependent release of glutamate frompresynaptic sites leads to the activation ofAMPA receptors and to the depolarization ofthe postsynaptic neuron. Depolarization canoccur by action potentials in the millisecondrange locally at the synapse. Depolarizationof postsynaptic neurons leads to the removalof NMDA receptor inhibition by Mgþþ andthen to Ca2þ influx through the receptor.This activates voltage-gated calcium channels(VGCCs), another source of synaptic Ca2þ

ions. This short-lived membrane depolari-zation process can be transformed to changesin gene expression and to long-term morpho-logical changes such as synaptic plasticity,leading to additional or more efficient synapses(Lamprecht and LeDoux 2004). It is thoughtthat by the modification of synapses the internal

representations are modified and thus memoryis enhanced, retained, or lost.

The role of NF-kB in the nervous systemhas gained interest because of its involvementin synaptic processes, neurotransmission, andneuroprotection. Furthermore, inducible NF-kB plays a crucial role in brain inflammationand neural stem cell proliferation. The role ofNF-kB in the cellular context of the nervoussystem is depicted in Figure 1.

All DNA-binding subunits of NF-kB havebeen detected within the CNS, and in theadult rodent brain the major DNA-bindingcomplexes are p50/p65 (Kaltschmidt et al.1993; Bakalkin et al. 1993; Schmidt-Ullrichet al. 1996; Meffert et al. 2003). In contrast, inthe developing nervous system complexes con-sisting of cRel/p65, p50/p65, and p50 homo-dimers were reported (Bakalkin et al. 1993).

NEURONS

Initially, constitutive (high basal) NF-kBactivity was found in glutamatergic neurons ofthe CNS, such as the hippocampus (granulecells and pyramidal neurons of CA1 andCA3) and cerebral cortex (layers 2, 4, and 5),by antibody staining (Kaltschmidt et al. 1993;Kaltschmidt et al. 1994; Kaltschmidt et al.1995), gelshift assays, and Western blotting.Transgenic reporter mouse models verifiedthese data and also showed constitutive NF-kBactivity in several rodent brain regions such asthe cerebral cortex, hippocampus, amygdala,olfactory lobes, cerebellum, and hypothalamus(Schmidt-Ullrich et al. 1996; Bhakar et al.2002). Here, constitutive NF-kB activity shallbe defined as activity that makes cells blue intransgenic reporter mice (mainly in neurons,but also endothelial cells). Constitutive NF-kBactivity can be suppressed by pharmacologicalinhibitors such as glutamate antagonists andL-type Ca2þ channel blockers (Lilienbaumand Israel 2003; Meffert et al. 2003). Thissuggests that constitutive NF-kB results fromphysiological basal synaptic transmission.Furthermore, constitutive NF-kB activityin endothelial cells, the roof plate (a dorsalsignaling center of the developing nervous

B. Kaltschmidt and C. Kaltschmidt

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Figure 1. The role of NF-kB within the cellular context of the nervous system. Constitutively activated NF-kB isdetected mostly in glutamatergic neurons (green nuclei), whereas NF-kB in glia has a lower basal activity and isheavily inducible (red nuclei). For details, see text.


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system), and floor plate (part of the neuraltube) is dependent on TRAF6, as shown bycrossing lacZ reporter mice with TRAF62/2

mice (Dickson et al. 2004). Inducible NF-kBwas detected in biochemically purified synapses(synaptosomes) (Kaltschmidt et al. 1993;Meberg et al. 1996; Meffert et al. 2003).Interestingly, analysis of TNFRI2/2, p652/2

double knockout mice showed no presence ofp65, p50, and IkB a and b in synapses. Thesedata suggest that p65 is the driving subunit forsynaptic localization and transport processes.It cannot be replaced by alternative subunitssuch as c-Rel or RelB.

A p65/GFP fusion protein can be retro-gradely transported from active synaptic sitesback to the nucleus (Wellmann et al. 2001;Meffert et al. 2003) after glutamatergic stimu-lation. This retrograde transport is dependenton the p65 nuclear localization signal (NLS)and involves a dynein–dynactin motor proteincomplex gliding on microtubules (Mikenberget al. 2007; Shrum et al. 2009). p65 NLS is alsoimportant for the contact of p65 and themotor protein complexes. In summary, theseobservations indicate that NF-kB has a centralrole in translating short-term synaptic eventsinto changes in gene expression.

LEARNING AND MEMORY

Genetic evidence� for the involvement of NF-kBin learning and memory was provided forthe first time in TNFRI2/2, p652/2 miceby Meffert et al. 2003. In a radial arm maze,TNFRI2/2, p652/2 mice made signifi-cantly more trial errors than control mice. Asecond, conditional mouse model uses aneuronal promoter-specific ablation of NF-kBin the basal forebrain (CamKII-tTA/tetOtnIkB-a). In this model, all NF-kB subunitswere repressed in vivo as measured by triple

transgenic lacZ reporter mice in hippocampalneurons (Fridmacher et al. 2003). These miceshowed impairments in spatial learning. Themice had to learn the position of a platformuseful for resting that was submersed withina water basin (Morris water maze). Mice expres-sing the super-repressor (tnIkB-a) showedreduced long-term potentiation (LTP) andlong term depression (LTD) (Kaltschmidt et al.2006). Furthermore, learning during trainingsessions in a Morris water maze stronglyinduced NF-kB binding activity in hippocam-pal extracts of wild-type mice (O’Mahony et al.2006). To obtain clues about NF-kB-regulatedchanges in gene expression, transcriptomeprofiling was performed. The catalytic subunita of the protein kinase A gene (PRKACA) wasidentified as a novel NF-kB target gene(Kaltschmidt et al. 2006). Recent research hasshown that protein kinase A (PKA)–CREBsignaling is an essential pathway for learningand memory (Kandel 2001). Connected withthis, repression of NF-kB in transgenic miceresulted in reduced PKA activity, leading to astrong reduction in forskolin-induced CREBphosphorylation (forskolin activates adenylcy-lase and thus raises intracellular cAMP levels).A functional NF-kB binding element was ident-ified within intron 2 of mouse and humanPKA genes (Kaltschmidt et al. 2006). Thesefindings identified a novel transcriptionalsignaling cascade in neurons in which NF-kBregulates the PKA/CREB pathway function inlearning and memory. Synapse density is animportant parameter for learning processes.After NF-kB ablation in the hippocampus,the density of synapses was strongly reducedwithin a hippocampal subfield, the stratumlucidum (Kaltschmidt et al., unpubl.). Inaddition, in mice with neuronal NF-kB ablationthe formation of axonal mossy fiber projectionswas impaired (Kaltschmidt et al. unpublished).These fibers normally connect granule cellswith CA3 pyramidal cells. To our knowledge,this is the first in vivo model showing NF-kBdependent structural plasticity.

Furthermore, dendritic arborization isregulated by NF-kB in peripheral and corticalneurons (Gutierrez et al. 2005). Thus both the

�This review focuses on evidence from genetic mousemodels. Readers interested in pharmacological approachesto NF-kB function in the nervous system should consultearlier reviews by Kaltschmidt et al. (2005), Meffert andBaltimore (2005), and Romano et al. (2006) for furtherinformation.





receiving structure (dendrite) and the sendingstructure (axon) seem to be regulated byNF-kB. Current literature suggests that dendri-tic and axonal outgrowth can be regulated byNF-kB in different ways in different neurons.In cortical neurons, dendritic arborization isrepressed by IkB (Gutierrez et al. 2005),whereas in hippocampal granule cells theaxonal outgrowth depends on NF-kB activity(Kaltschmidt et al. unpublished). An importantregion of neuronal information processing isthe axon initial segment (AIS). This region isextremely rich in membrane-embeddedvoltage-gated sodium channels and is the axonpotential generating region. Interestingly, thephosphorylated forms of IKK-1, IKK-2, andIkB-a are concentrated within the AIS(Schultz et al. 2006). The node of Ranvier isalso enriched in action potential generatingsodium channels and also in phosphorylatedforms of IKK 1, 2, and IkB-a (Politi et al.2008). The localization of phosphorylatedNF-kB regulators might indicate the majorsites of intracellular NF-kB activation. Pharma-cological blockade of IKK function in culturedhippocampal neurons interfered with the local-ization of phosphorylated IkB-a and IKKwithin the AIS (Sanchez-Ponce et al. 2008). Insummary, these data show that NF-kB is animportant regulator of neuronal morphologyand shapes brain structures that are importantfor learning and memory.

A critical function of NF-kB in inhibitoryGABAergic interneurons was observed in arecent transgenic mouse model (O’Mahonyet al. 2006). Cell-type specific expression ofsuper-repressor IkB-a (Prion promoter-driventTA/tetO super-repressor IkB-a) in bothinhibitory GABAergic interneurons (robustexpression) and hippocampal excitatory gluta-matergic neurons (low level expression) resul-ted in a phenotype opposite to that resultingfrom the inhibition of NF-kB in glutamatergicneurons only (Kaltschmidt et al. 2006). Expre-ssion of glutamate decarboxylase (GAD65), arate-limiting enzyme required for the synthesisof the inhibitory neurotransmitter, GABA, wasdown-regulated in these mice. Super-repressorIkB mice completed a radial maze in less time

and made fewer errors than control mice, indi-cating enhanced spatial learning and memory.Furthermore, LTP was enhanced. These findingsmight be explained by a model in whichexcitatory neurons are the motor of learningand GABAergic neurons provide the brake.A blockade of the brake (by expression of thesuper-repressor) would result in overactivationof the motor (excitatory neurons) and wouldexplain the enhanced learning. Consistentwith this is the observation that Baclofen, apharmacological agonist of GABA, negativelyaffected learning (McNamara and Skelton1996). A major advantage of super-repressorexpression is the inhibition of all NF-kBsubunits. On the other hand, overexpressionmight have unexpected gain of functioneffects. The p50–/– mice had defects in noveltask acquisition (Kassed et al. 2002), decreasedanxiety (Kassed and Herkenham 2004), andreduced short-term memory (Denis-Doniniet al. 2008). Homodimers of p50, whichlack a transactivation domain, might act as arepressor of gene transcription on a set ofspecific promoters. Thus, some of the effectsobserved in p502/2 animals might be inaddition to the loss of p50 function, a result ofthe derepression of NF-kB target genes.

The function of NF-kB was analyzed in fear-conditioning paradigms, a form of learning inwhich an unconditioned stimulus like a toneis coupled to noxious stimulation such as elec-tric shock. Fear-conditioning seems to dependon the amygdala, a region in which constitutiveNF-kB activity has already been reported.Moreover, a c-Rel knockout was analyzed in acued fear-conditioning paradigm and analyzed24 h later. No amygdala-dependent changes inlong-term memory were reported in c-Relknockout animals (Levenson et al. 2004).The presentation of landmarks in the fear-conditioning paradigm gave quite differentresults, with deficits in freezing being observed.In addition, c-Rel2/2 mice showed loweractivity in an open field test. Bioinformaticanalysis suggested an overrepresentation ofNF-kB binding sites in the promoters of genespotentially involved in memory consolidation(Levenson et al. 2004), but this was not tested





experimentally with, for example, ChIP. Like-wise, a recent bioinformatic study has suggestedan enrichment of NF-kB and E2F binding sitesin genes potentially important for the develop-ment of neurons from neural precursors, andthus additional experiments are necessary(Greco et al. 2008).

Recently, a pharmacological study usingDDTC (Diethyldithiocarbamate) and SN50(a cyclic peptide, spanning the NLS of p50)showed impaired memory reconsolidation(Lubin and Sweatt 2007).

Overall, the results of behavioral analyses ofmice with reduced NF-kB activity in brain (seeTable 1) can be summarized as follows: Deletionof DNA-binding subunits in all cell types,including neurons and glia, resulted in lowerperformance in different behavioral tests. Thisphenotype was also seen following repression

of NF-kB in glutamatergic neurons (CamKIItTA / tetO super-repressor), suggesting thatNF-kB function in glutamatergic neuronsis responsible for learning and memory.On the other hand, changing the balance ofglutamatergic and GABAergic neurons bythe higher expression of super-repressor inGABAergic neurons enhances the learning ofspatial clues.

HYPOTHALAMUS

Previous reports analyzing transgenic NF-kBlacZ reporter mice have described constitutiveNF-kB activity within the hypothalamus(Schmidt-Ullrich et al. 1996; Bhakar et al.2002). The hypothalamus contains the domi-nant neuroendocrine center for the control offood intake and energy expenditure. Recently,

Table 1. Genetic mouse models interfering with NF-kB activity in the nervous system

Genotype

Cell type

afflicted Cognitive defect Additional phenotype References

p502/2 All Defect in novel taskacquisition;decreasedanxiety; reducedshort-termmemory

Reducedneuroprotection;hearing loss; reducedneurogenesis;reduced ischemicdamage; impairedacute andinflammatorynociception

Yu et al. 1999; Yu et al.2000; Kassed et al.2002; Kassed andHerkenham 2004;Duckworth et al.2006; Denis-Doniniet al. 2008;Schneider et al. 1999,Niederbergeret al. 2007

p652/2 Isolated sensoryneurons

na� Reducedneuroprotection

Middleton et al. 2000

p652/2 IsolatedSchwann cells

na� Reduced myelination ofperipheral nerves;

Nickols et al. 2003

p652/2

/TnfrI2/2

All Delayed spatiallearning inradial maze

No synaptic NF-kB Meffert et al. 2003

CamKII tTA/tetOsuper-repressorIkB-a

Glutamatergicforebrainneurons

Impairments inspatial memory;reduced LTP andLTD

Reducedneuroprotection;decreased PKAexpression andP-CREB

Fridmacher et al. 2003;Kaltschmidt et al.2006

Prion-tTA/tetOsuper-repressorIkB-a

Glutamatergicandinhibitoryneurons

Enhanced spatiallearning;enhanced LTD

Reduced GAD65expression

O’Mahony et al. 2006

(Continued)





it was reported that a high fat chow increasedthe already activated NF-kB in the hypothala-mus neurons two- to fourfold (De Souza et al.2005). Zhang and coworkers reported highexpression of IKK-2 and IkB-a in neurons ofthe mediobasal hypothalamus, a brain regioninvolved in nutrition sensing. High fat chow,acute administration of glucose, or intraventri-cular injection of oleic acid hyper-activatedNF-kB two- to fourfold (Zhang et al. 2008).Tissue-specific knockout of IKK-2 with NestinCRE mice or virally transmitted CRE (lentivirusor adenovirus) injected into the hypothalamusreduced food consumption and weight gain intransgenic mice fed with high fat chow. In

contrast, the neural expression of a constitutiveform of IKK-2 enhanced weight gain after ahigh-fat diet and impaired hypothalamic sensi-tivity to insulin and leptin. Ablation of IKK-2 inspecific AGRP hypothalamic neurons protectedagainst induction of central insulin and leptinresistance after a high-fat diet. Zhang and co-workers identified SOCS3 (a suppressor of cyto-kine signaling) as a novel NF-kB target gene anda crucial regulator of diet-induced obesity.Hypothalamic neurons are now also consideredto form a key center involved in sleep regulation(Mignot et al. 2002). Sleep-inducing substancesinclude proinflammatory cytokines such asTNF and IL-1. TNFR1 knockout animals

Table 1. Continued

Genotype

Cell type

afflicted Cognitive defect Additional phenotype References

GFAP-super-repressorIkB-a

Glia: astrocytes Deficits in learningonly in females:delayed spatiallearning,impaired cuedfear memory

LTP reduced in females;LTP enhanced inmales; reduction ofmGluR5 in females;better recovery afterspinal cord injury;reduced painsensitivity

Bracchi-Ricard et al.2008; Brambilla et al.2005

c-Rel2/2 All Impaired latephase LTD;impairedlong-termmemory;impaired cuedfear memory

Reducedneuroprotection

Pizzi et al. 2002;Levenson et al. 2004;Ahn et al. 2008

LysM-Cre/IKK-2FL/FL

Glia: microglia;macrophages

na� 30% reduction ofneuronal death:10-fold reducedinfarct size afterMCAO

Cho et al. 2008

Nestin-Cre/IKK-2FL/FL

Neural (glia andneuron)

na� 25% reduction of infarctsize after MCAO;amelioration of EAE

Herrmann et al. 2005;van Loo et al. 2006

Nestin-Cre/Ikk-1FL/FL


na� No effect on EAE van Loo et al. 2006

Nestin-Cre/NemoFL/FL


na� Amelioration of EAE van Loo et al. 2006

NSE-SR-IkB-a Neuronal na� Improved LPS-inducedhypothermia andsurvival

Juttler et al. 2007

na�: not analyzed.





cannot sleep in response to TNF-a application(Fang et al. 1997).

A unique population of neurons imm-unoreactive for the p65 subunit of NF-kB waspreviously localized within the caudal dorsolat-eral hypothalamus of rats.

In relation to this, analysis of NF-kB-drivenlacZ reporter mice has shown that sleep depri-vation increases the number of cells expressingNF-kB-dependent b-galactosidase in the mag-nocellular lateral hypothalamus and zonaincerta dorsal, as well as the adjacent subthala-mus in transgenic mice (Brandt et al. 2004).Intracerebral injection of cell permeableNF-kB-inhibiting peptide spanning the NLSof p50 (SN50) inhibited IL-1-induced sleep inrats and rabbits (Kubota et al. 2000).LPS-induced hypothermia activated kB lacZexpression in brain, and neuronal expressionof the IkB[a] super-repressor suppressedhypothermia and increased survival (Juttleret al. 2007).

NEUROPROTECTION

Initially observed in cerebellar granule neurons,a subtoxic dose of a neurotoxin (Ab or Feþþ)led to long-lasting NF-kB activation. This wasprotective against a higher dose of neurotoxins(Kaltschmidt et al. 1999; Kaltschmidt et al.2002). This process was described by the 16th-century physician Theophrastus Bombastusvon Hohenheim (Paracelsus): “All Ding seinGift allein die Dosis machts” (all things arepoisons only the dose is important). Precon-ditioning or hormesis (Mattson 2008) wasdependent on activated NF-kB and might be asubcellular vaccination strategy, as suggestedby D. Baltimore (Baltimore 1988). Further invitro studies provided evidence that activationof NF-kB can protect neurons against amyloidb peptide toxicity (Barger et al. 1995) andexcitotoxic or oxidative stress (Goodman andMattson 1996; Mattson et al. 1997). Adenoviru-ses expressing super-repressor or dominant-negative NIK reduced survival of corticalneurons, whereas overexpression of p65 pro-tected cortical neurons against apoptotic celldeath induced by etopside (Bhakar et al.

2002). In vivo experiments in models of brainpreconditioning with kainate or ischemia orlinolenic acid showed NF-kB dependent protec-tion against neuronal death (Blondeau et al.2001). Later, transgenic inhibition of NF-kBby neuronal overexpression of the IkB[a] super-repressor decreased neuroprotection afterkainic acid or Feþþ application (Fridmacheret al. 2003). In hippocampal acute slicesderived from cRel2/2 mice treatment withNMDA and IL-1b increased neurodegeneration(Pizzi et al. 2002). Surprisingly, under wild-typeconditions no c-Rel containing DNA bindingcomplexes were detected in adult brain (Kaltsch-midt et al. 1993; Schmidt-Ullrich et al. 1996;Bakalkin et al. 1993; Meffert et al. 2003).Only activation of metabotropic glutamatereceptors with, for example, 1 mM (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) un-covered the protective action of c-Rel, whereasRNA against the c-Rel or c-Rel2/2 genotypehad no cell death enhancing effect in neuronswithout pharmacological activation of themetabotropic glutamate receptor (Pizzi et al.2005). Injection of neurotoxins in p502/2

mice such as trimethyltin (Kassed et al. 2004),excitotoxins (Yu et al. 1999), or mitochondrialtoxin 3-nitropropionic acid (Yu et al. 2000)increased neuronal damage. Furthermore,p502/2 animals suffered from hearing lossbecause of degeneration of spiral ganglionneurons (Lang et al. 2006). Ischemia inducedin p502/2 mice showed a clear neuroprotec-tive role of NF-kB in the hippocampus andstriatum, in which degenerating neurons weredetected 4 d after 1 h of ischemia (MCAO para-digm) (Duckworth et al. 2006). Degeneratingneurons did not show NF-kB-dependent repor-ter gene expression, and in addition p502/2

mice experienced a 2.4-fold increase in post-operative death in comparison to controls(Duckworth et al. 2006). At a first glance,these data appear to conflict with reports ofreduced infarct volume in p502/2 mice anda 25% reduction in models with neuronal- orbrain-specific IKK-2 ablation (Schneider et al.1999). However, a recent analysis showed a10-fold reduced infarct size in mice withmicroglial-specific IKK-2 ablation (Cho et al.





2008). Thus NF-kB-dependent microglia acti-vation might be a crucial contributor to ische-mia. Unfortunately, neuroprotective strategiesdeveloped in animal models do not workin human stroke (Rother 2008). There couldbe many reasons for this, such as translationarrest and/or increased vulnerability inhuman white matter. A summary of the neuro-protective effects observed in genetic models ispresented in Table 1.

GLIA

No constitutive NF-kB activity was detectedin glial cells of untreated animals (Schmidt-Ullrich et al. 1996; Bhakar et al. 2002), sugge-sting that inducible NF-kB activity might belinked to pathological events. Initially, it wasreported that NF-kB activated in astrocytes viaamyloid b peptide (Ab) led to the productionof nitric oxide (Akama et al. 1998). This astro-glial neurodegenerative role of Ab contrastswith the neuroprotective activation of NF-kBin neurons by nanomolar concentrations ofAb (see previous discussion) (Kaltschmidtet al. 1997; Kaltschmidt et al. 1999). GFAPpromoter-driven super-repressor IkB expre-ssion was present in astrocytes of brain, spinalcord, and peripheral nerves (Brambilla et al.2005). Spinal cord contusion injury increasedGFAP expression in activated astrocytes at thelesion site. Activated astrocytes release inflam-matory mediators such as chemokines and cyto-kines. Unexpectedly, expression of the NF-kBtarget gene IL-6 was significantly up-regulatedin GFAP super-repressor mice, whereas TNFexpression remained unchanged (Brambillaet al. 2005). However, the expression of the che-mokines CXCL10 and CCL2 was significantlydown-regulated in comparison to wild-typemice after spinal-cord injury in GFAP SRmice. Outcome after spinal-cord injury, asmeasured by locomoter activity, was signi-ficantly ameliorated, suggesting that inducibleastrocytic NF-kB does not function in cellsurvival but exacerbates chemokine-drivendefects in spinal-cord recovery. Likewise, NF-kB inhibition resulted in reduced glial scarring,

which perhaps allows better axon regeneration(Brambilla et al. 2005). Axotomy of the entorh-inal perforant path projection resulted in astro-cytic STAT2 up-regulation and phosphorylationand concomitant expression of CCL2. Usingthe same mouse model (GFAP-SR), it was shownthat the lesion-induced expression of CCL2 andSTAT2 was significantly blunted (Khorooshiet al. 2008). These results suggest that NF-kB sig-naling in astrocytes might regulate chemokine-induced infiltration of immune cells into thelesioned brain. Similarly, Nemo and IKK-2 del-etion within the CNS resulted in a significantreduction of infiltration of inflammatory cells(van Loo et al. 2006). Experimental autoimmuneencephalomyelitis (EAE), a model of humanmultiple sclerosis, was ameliorated after Nemoor IKK-2 deletion in astrocytes. A 10-fold reduc-tion of nuclear p65 in astrocytes after IL-1 orTNF treatment resulted in a more than 10%reduction in chemokine production (CXCL10).These data underscore the pivotal role of astro-cytes in EAE and the recruitment of infiltratinginflammatory cells. The role of microglia in neu-roprotection or neurodegeneration is heavilydebated. Recently, analysis of LysM-Cre/IKKFL/

FL mice showed 36% deletion of the IKK b

gene in cultured neonatal microglia (Cho et al.2008), but only 4% deletion in adult microglia.Kainic acid injection resulted in the deletion ofIKK-2 in 73% of microglial cells. Kainic acid-induced cell death was reduced, presumably bydecreased activation of NF-kB-regulated micro-glial proinflammatory genes, such as TNF-aand IL-1b. A remarkable result was the 10-foldreduction of the infarct area after MCAO (Choet al. 2008). In summary, IKK-2-mediatedmicroglia activation potentiated neuronalexcitotoxicity.

PAIN

Recently, a role of glial NF-kB in pain hasemerged. Pain can arise from the activation ofspecific high-threshold PNS neurons (nocicep-tors) and could serve as a sensing mechanism toprevent further damage. However, clinical paincan arise from damage to the nervous system(neuropathic pain) or chronic inflammation





(inflammatory pain). Analysis of p502/2

mice revealed an impairment of acute andinflammatory nociception (Niederberger et al.2007). Recent data suggest an importantrole of astroglial NF-kB in pain perception:Inhibition of the expression of pain mediators(TNF-a, IL-6, and iNOS) by lentiviral deliveryof IkB-a super-repressor injected into thedorsal horn reduced pain (Meunier et al.2007). Similarly, GFAP super-repressor micehave decreased formalin pain sensation (Fuet al. 2007).

NEURAL STEM CELLS

During adulthood, neural stem cells continue toproliferate in the subventricular zone (SVZ) andwithin the hilus of the hippocampus. In adultneural stem cells isolated from the SVZ, p65regulates proliferation via NF-kB target genesc-myc and cylin D1 (Widera et al. 2006). Fur-thermore, proliferation was strongly inhibitedin neural stem cells prepared from the gangli-onic eminence of p502/2 p652/2 embryos(Young et al. 2006). Expression of p65 and p50persists into adulthood, particularly in subven-tricular zone astrocyte-like cells and inmigrating neuronal precursors, respectively.

In particular, p65 and p50 are expressed inradial glial cells, in migrating neuronal precur-sors, and in a population belonging to the astro-cytic lineage (Shingo et al. 2001). RelB, on theother hand, is only expressed in migrating neur-onal precursors, whereas c-Rel is present in afew cells located at the edges of the rostralmigratory stream (Denis-Donini et al. 2005).

In p502/2 animals, no defects in prolifer-ation of hippocampal stem cells was detected(Denis-Donini et al. 2008). However, survivalof neural progenitors after 21 days post BrdUinjection was significantly reduced inp502/2 animals.

Taken together, current literature suggeststhat NF-kB fulfils very different functions indifferent cell types. A lot of controversial resultswere obtained in the last decade by neglectingthe cell type-specific effect of NF-kB and theinterplay between different neuronal cell typeswith glia.

In this line, the generation and analysis ofsophisticated cell type-specific knockoutmodels might be necessary to unravel all ofthe mysteries of NF-kB in the nervous system.

ABBREVIATIONS

PNS: peripheral nervous systemCNS: central nervous systemMCAO: middle cerebral artery occlusionEAE: experimental autoimmune

encephalomyelitisVGCC: voltage-gated calcium channelsGABA: g-aminobutyric acidAIS: axon initial segmentChIP: chromatin immunoprecipitationLTD: long term depressionLTP: long term potentiation

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2009; doi: 10.1101/cshperspect.a001271Cold Spring Harb Perspect Biol Barbara Kaltschmidt and Christian Kaltschmidt

B in the Nervous SystemκNF-

Subject Collection NF-kB

BκRegulators of NF-Use of Forward Genetics to Discover Novel

Tao Lu and George R. Stark

BκOncogenic Activation of NF-Louis M. Staudt

B ResponseκSelectivity of the NF-Ranjan Sen and Stephen T. Smale System

B SignalingκThe Regulatory Logic of the NF-

Ellen O'Dea and Alexander HoffmannB in the Nervous SystemκNF-

Barbara Kaltschmidt and Christian Kaltschmidt Development and FunctionB Pathway in LymphocyteκRoles of the NF-

Steve Gerondakis and Ulrich SiebenlistB: Regulation by UbiquitinationκSignaling to NF-

Ingrid E. Wertz and Vishva M. Dixit ActivationBκThe IKK Complex, a Central Regulator of NF-

Alain Israël

BκNF-Ubiquitination and Degradation of the Inhibitors of

Schueler-Furman, et al.Naama Kanarek, Nir London, Ora

B in the Nervous SystemκNF-Barbara Kaltschmidt and Christian Kaltschmidt

Signaling ModuleBκA Structural Guide to Proteins of the NF-

Tom Huxford and Gourisankar GhoshInflammation

B Pathway inκThe Nuclear Factor NF-

Toby LawrenceDrosophilaB in the Immune Response of κNF-

Charles Hetru and Jules A. Hoffmann and CancerB as a Critical Link Between InflammationκNF-

Michael Karin

Responses by Chromatin OrganizationB-dependent TranscriptionalκControl of NF-

Gioacchino NatoliProteins

BκSpecification of DNA Binding Activity of NF-

Fengyi Wan and Michael J. Lenardo

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NF-kB in the Nervous Systemcshperspectives.cshlp.org/content/1/3/a001271.full.pdf · peripheral nerves are part of the PNS. The CNS coordinates different tasks: integration of all