Page - 36 - in Advances in Neuroimmunology

BrainSci. 2016,6, 6 increase thereleaseofglutamate fromastrocytes,maintainglutamate levels throughtheblockingof glutamate transporters [96] andmodulate theexpressionofGlut-1andGlut-2. All theseeffectsby TNF-α result in the increase in theconcentrationofglutamate in thesynapticcleft,whichmayhave aninfluenceonthemagnitudeofLTPpost-hypoxia.UsingarobustLTP-inducingstimulusprotocolwe havebeenable todemonstrateasignificantenhancingeffectofTNF-αonLTPposthypoxiabutonly in thedentategyrusof thehippocampus[102]. In thepresenceofDMOG(anon-specificPHDinhibitor) thisenhancementofLTPwasstill evidentperhaps indicatinganovelHIF/PHD-independenteffectof TNF-α [102]. Figure3.PutativesignalingpathwaysactivatedafterHFS-andTBS-inducedLTP.HFS-inducedLTP maybedependentonthebreakdownof51AMPintoadenosine.Adenosineactivates theA2ARreceptor leadingtocAMPandPKAactivation. TBS-inducedLTPinvolves the influxofCa2+ andsubsequent activation of calpain-1. The activation of calpain-1 leads to a calapin-1-mediated suprachiasmatic nucleuscircadianoscillatoryproteindegradationandERKactivation. ExogenousTNF-α inhibitsLTP inducedbyTBSonly.Duringhypoxia,TNF-αmayhavepotentiatingeffectonHFS-inducedLTPbut notTBS. 8.Conclusions Hypoxia isoneof thekeycomponents,whichcanarise fromneuropathologicalconditionssuchas stroke,Parkinson’sorAlzheimer’sdisease.Hypoxiceventscancause thereleaseofpro-inflammatory cytokines fromneurons andglial cells, such asTNF-α,which can lead to further neurotoxicity or indeed neuroprotection in the brain. However, the effects of TNF-α on neurons during de- and re-oxygenationofneurons is largelyunknown.Manystudieshavenowshownthatpro-inflammatory cytokines, suchasTNF-α,playakeyrole in theregulationofsynaptic transmissionandplasticity in theabsenceandpresenceofacutehypoxia,especiallywithin thehippocampus. Themechanismsby whichelevated levelsofTNF-αhaveanenhancingordetrimental effectonsynaptic signalingand synapticplasticity in thepresenceorafterahypoxicevent remains tobeelucidated. Acknowledgments:Wewould like to thankIrishAidandUniversityCollegeDublin forfinancial support. Author Contributions: Gatambwa Mukandala wrote the sections on TNF- and hypoxia and hypoxia and neuroinflammation in theCNSandconceivedanddesignedexperiments referredto in thereview.RonanTynan 36