Page - 35 - in Advances in Neuroimmunology

BrainSci. 2016,6, 6 6.TNF-αandSynapticPlasticity AgrowingbodyofevidencehashighlightedtheroleofTNF-α inglutamatergicsynapticplasticity andscaling. IthasbeenshownthatTNF-αhasan inhibitoryeffectonLTPinboththeCA1anddentate gyrus [76,86–89]. Studies initiallycarriedoutbyTancredi et al. (1992) [90] showedaninhibitoryeffect ofTNF-αonLTPinduction in theCA1region,whichwasconcentration-dependent.However, they demonstratedthatshort-termapplicationofTNF-α (>50min)didnotaffectLTP.Thesefindingsand othershighlight thevariousparameters involved in the regulatory role that this cytokineplays in synapticplasticity. The inhibitoryactionsofTNF-αonLTPhavebeenshowntobemediatedthrough the signalingpathways, P38MAPkinase and JNK [91]. Butler et al. (2004) [88] reported that the inhibitionofLTPbyTNF-αwas in factabiphasic response. SB203580,aP38MAPKinhibitor,blocked theearly inhibitionofLTPbyTNF-αbutdidnotreverse its late inhibition(3hfollowinginduction), possibly due to the requirement for new protein synthesis. Using antagonists formetabotropic glutamatereceptor5 (mGluR5)andryanodine,apotential role formetabotropicglutamatereceptors andryanodinesensitive intracellularCa2+ stores inTNF-αmediated inhibitionofLTPhavealsobeen proposed[87]. Otherstudieshaveprovidedevidence thatexogenousapplicationofTNF-αwhilstnot inhibiting LTPintheCA1regionof thehippocampusmayalterhomeostaticplasticity (synaptic scaling) rather than synaptic plasticity [92]. These studies have shown that glia released TNF-α is required for synaptic scaling throughAMPARtrafficking to themembrane [92–94]. Othershave reported that the increase inAMPARexpressiononthecell surface ismediated throughtheP13kinasepathway and theAMPARs traffickedwere lacking theGLR-2 subunit. SinceLTP isdependent on synaptic glutamate it is also interesting to note that TNF-αhas been shown to increase glutamate release fromastrocytes [95], blockglutamate transporters [96], andalsomayhaveamodulatory effect on the expression of GLT-1 and GLT-2. These effects combined may result in increased glutamate concentrations in the synaptic cleft [97,98]. TNFR1, but not TNFR2,mayplay an important role inAMPARlocalizationonthemembraneofcorticalneurons.DeletionofTNFR1resulted inadecrease ofAMPARclusteringonthesynapticmembrane,whichwasnotrescuedbyexogenousapplication ofTNF-α [99]. Theseobservations indicateapotential therapeuticapproachforTNF-αviaTNFR1in mediatingAMPARexcitotoxicity.Glutamatergicgliotransmission isan important stimulatory input to excitatorysynapsesandithasbeenshownthatTNF-α isamodulatorof thisprocess in thedentate gyrus [100].Manyof thediscrepanciesobservedwithregardto theeffectsofTNF-αonLTPmaybe regionspecificor indeeddependonthe inductionprotocolusedto induceLTP.Therearemanyfactors regulating themagnitudeofLTPinducedbydifferentparameterssuchashighfrequencystimulation andthetaburst stimulation[101] (Figure3). Recently,wehaveshownthat thestimulationparameters used to induceLTPmayhave an influenceonTNF-α’s ability to inhibit LTP [102]. TNF-αhasno inhibitoryeffectonLTPwheninducedwithprolongedhighfrequencystimulation(HFS)whereas full inhibitionwasobservedwhenLTPwas inducedbythetaburst stimulation(TBS).Figure3 illustrates a potentialmechanism thatmight explain this discrepancywhereby TBSmay trigger alternative signalingcascades toHFSthatcanbemodulatedbyTNF-α. 7.TNF-α,HypoxiaandSynapticPlasticity Hippocampalslicesexposedtoacutehypoxiamayrecoverwhenoxygenisre-introduced.Recently ithasbeenshownthat in thepresenceofTNF-α there isan impairment in therecoveryof synaptic transmission in the CA1 region post-hypoxia [77]. Conversely, hypoxia has also been shown to increase intercellular Ca2+ levels and activate calmodulin-dependent protein kinase II (CaMKII) through a TNF-α independentmechanism [103]. However CaMKII is also capable of activating thePI3K-PKCλ-AMPARsignalingpathway. TNF-αhas been found toplay roles in cell adhesion up-regulation,disruptionof thebloodbrainbarrierandisakeycomponent for theparticipationof glial cells in thephysiological controlof synaptic transmissionandplasticity throughthereleaseof glutamate, aprocessknownasglutamatergicgliotranmission [100,104]. TNF-αhasbeenshownto 35