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brain sciences Review TheEffectsofHypoxiaandInflammationonSynaptic SignalingintheNS GatambwaMukandala,RonanTynan,SineadLaniganandJohnJ.O’Connor* UCDSchoolofBiomolecularandBiomedicalScience,UCDConwayInstituteofBiomolecularandBiomedical Research,Belfield,Dublin4, Ireland;Gatambwa.mukandala@ucdconnect.ie (G.M.); ronan.tynan@ucdconnect.ie (R.T.); sinead.lanigan@ucdconnect.ie (S.L.) * Correspondence: john.oconnor@ucd.ie;Tel.:+353-1-716-6765 AcademicEditor:DonnaGruol Received: 17December2015;Accepted: 2February2016;Published: 17February2016 Abstract:Normalbrain function ishighlydependentonoxygenandnutrientsupplyandwhenthe demandforoxygenexceeds its supply,hypoxia is induced.Acuteepisodesofhypoxiamaycause adepression insynapticactivity inmanybrainregions,whilstprolongedexposure tohypoxia leads toneuronalcell lossanddeath.Acute inadequateoxygensupplymaycauseanaerobicmetabolism andincreasedrespiration inanattempt to increaseoxygenintakewhilst chronichypoxiamaygive rise toangiogenesisanderythropoiesis inorder topromoteoxygendelivery toperipheral tissues. Theeffectsofhypoxiaonneuronal tissueareexacerbatedbythereleaseofmanyinflammatoryagents fromgliaandneuronalcells. Cytokines, suchasTNF-α, andIL-1βareknowntobereleasedduring theearlystagesofhypoxia, causingeither localorsystemic inflammation,whichcanresult incell death.Anothergrowingbodyofevidencesuggests that inflammationcanresult inneuroprotection, suchaspreconditioningtocerebral ischemia, causing ischemic tolerance. In the followingreviewwe discuss theeffectsofacuteandchronichypoxiaandthereleaseofpro-inflammatorycytokineson synaptic transmissionandplasticity in thecentralnervoussystem. Specificallywediscuss theeffects of thepro-inflammatoryagentTNF-αduringahypoxicevent. Keywords: hypoxia; TNF-α; adenosine; HIF-1α; hippocampus; long-term potentiation; prolyl hydroxylase inhibitor 1. Introduction In the central nervous system,hypoxiaoccurswhen there is an inadequate supplyofoxygen toneuronal tissue. Duringacutehypoxiamultipleoxygensensorsaredeployedallowingneurons toadapt to the response. These responses tohypoxia includesynaptic signalingdecreasesusually as a result of anerobicmetabolism changeswhilst chronic hypoxiamay give rise tomore severe perturbationsofsynaptic transmissionandtheactivationof transcriptionfactors that regulateoxygen homoestasis [1]. Differentneuronsadapt toadecreasedoxygensupply to thebrain inmanyways, reflectingthediverseroleofneuronal functionsandalso theextentof thehypoxiaexperienced. It is nowknownthatanhypoxicevent inbraintissuecancauseATPtodropbyasmuchas90%inless than 5min.Additionally,oxygen-sensitive ionchannals includingNa+andK+areactivatedbringingabout changes inexcitationandinhibitionofneuronalandglial cells [2]. Depolarisationofcellsmayalso takeplacecausingtheuptakeofNa+andCl´ intocells followedbypassive influxofwater, resulting inswellingandoedema[2].Hypoxic insultsmayalsoactivatevoltage-gatedCa2+ andK+ ionchannels andglutamate transporters, eventually causingexcessglutamate to spill into the synaptic regions causingexcitotoxicity.Ontheotherhand,manyof the long-termhypoxic responsesaremediatedby hypoxia inducible factors (HIF), suchasHIF-1α [3,4].HIF-1α isauniversallyexpressedtranscriptional BrainSci. 2016,6, 6 29 www.mdpi.com/journal/brainsci