Seite - 32 - in Advances in Neuroimmunology

BrainSci. 2016,6, 6 to a reduction in the levels of the transcription factor cAMP response element-binding protein (CREB) in its phosphorylated form [29]. This reduction in activatedCREB leads to a lowering of CREBtranscriptional targets, suchasbrain-derivedneurotrophic factor (BDNF), causingcognitive dysfunction[30]. TheCIH-inducedcognitivedysfunctionwasshowntoberepairedthroughexogenous applicationofBDNFtothehypoxiccell [30]. Perinatalhypoxiceventsmayalso leadto increases in excitability inhippocampalregions. Theseeventsusuallyoccurafterasphyxiaevents justafterbirth andcanleadto longtermsynapticchanges.Changes inexcitability insomelocalbrainregionssuch as theCA1regionhavealsobeennoted [31]. Thepursuantneonatal seizuresmayberelated to the phosphorylationof theAMPAGLUA1 receptors on serine 183 and serine 845. Thismayenhance AMPAreceptorexcitatorypostsynapticcurrents (EPSCs)whichallowsforadecrease inthepercentage of silent synapses andan increase inAMPAreceptor function [32]. This loss of silent synapses is thought tobe themechanism,whichattenuatessynapticplasticity inadult life [33]. Incritical casesof hypoxia-re-oxygenationthebrain loses theability to formnewmemories. Thisanterogradeamnesia is decoupledfromthehippocampusanditsprimarilycausedbyadenosineup-regulationofcaspase1and thenIL-1β in theamygdala [34]. Theseeffectswereshownto lastuptofivehoursafter re-oxygenation with caspase inhibitors, such asYVAD-CMK, able to shorten the recovery time [34]. The links of hypoxiatocognitivedisorders,aswellasabilitytocauseneuronalapoptosis throughhyper-excitability, displays the importanceofunderstandinghypoxiaandpreventing its long-termeffects. 3.HypoxiaandSynapticPlasticity Aspreviouslymentioned,hippocampalneuronexposuretohypoxiamayleadtocognitivedeficits duetosynapticplasticity impairments [35].Manystudieshave investigatedtherelationshipbetween oxygendeprivationandsynapticplasticity. Earlystudies indicated thatbriefperiodsofhypoxiacould disrupt long-termpotentiation(LTP) in theCA1hippocampusandthat thiseffectcouldbereproduced withbriefapplicationofadenosineprior to the inductionofLTP[36–38]. Itwas laterdiscoveredthat abriefanoxicepisode,asopposedtohypoxia,appliedtobrainslices, couldgenerateanewtypeof LTPalthoughstill voltage-,NMDA- [39],proteinkinaseC(PKC)-andNO-dependent [40–42]. It is proposedthat it is there-oxygenationandnot initialde-oxygenationofneuronsandthesubsequent highconcentrationofglutamatethatinfactcausestheexcessiveactivationofNMDARsandsubsequent large influxofCa2+ [43]. It has alsobeen shown that chemically-inducedhypoxiawith theuseof PHD inhibitors, and thus hypoxiamimetics,whilst havingno effect on synaptic signaling at low concentrationsper se, could inhibitLTPinthehippocampus[44,45].Applicationof the ironchelator deferoxaminemesylate (DFO)ordimethyloxaloglycine (DMOG),bothnon-specificpharmacological inhibitors of PHD, and thus increasers of HIF-1α expression [46] could impair LTP in the CA1 hippocampus [4,44,45,47]. Interestingly the application ofDMOG to the dentate gyrus region of hippocampal slicesdidnot impairLTP [29]. It is believed that these effects of PHD inhibitors are notHIF-dependent. There is also increasingevidence for a role forCIH in synapticplasticity and specificallyLTP. Initial reports inearly2000demonstrated thatCIHtreatedanimalsdemonstrated impairedLTPin isolatedrathippocampalslices [48,49].Morerecently tworeportshaveput forward evidenceforarole forBDNFinthis impairment [30,50]. TheyfoundthatapplicationofBDNFreversed the IH-induced impairmentofLTP. Inourownlaboratorieswehave implicatedarole forPHDsin this inhibitionofLTPbyintermittenthypoxia [29]. 4.HypoxiaandNeuroinflammationintheCNS During an ischemic stroke and resulting hypoxia, inflammatory cytokines are released by microglia,neuronsandastrocyteswithglutamate largelyreleasedbyneurons. Theup-regulationof pro-inflammatorycytokines throughtheactivationofmicrogliaandastrocytes in thebraincontribute a great deal to ischemic brain damage [51]. During hypoxia, HIF-1α binds toHRE like binding sitesallowing for theup-regulationofcytokines, suchas IL-β, IL-6, IL-8, andTNF-α.Mutations in either theHIF-1αgene or its binding site at thepromoter inhibit this cytokineup-regulation [46]. 32