Page - 31 - in Advances in Neuroimmunology

BrainSci. 2016,6, 6 reductionofpostsynapticpotentials [19]. Ithasalsobeenshownthat theA1Rbindingofadenosine inhibitsNMDAreceptoractivation[20].Creationofknockoutmicewith thedeletionofpresynaptic A1Rs, uncovered the neuroprotective role that adenosine receptor binding plays in the hypoxic response [21]. Synapticdepressionof theexcitatorypost-synapticpotential (EPSP)wasattenuated allowingactivationofglutamatergicNMDAreceptorsandincreasingthe likelihoodforexcitotoxicity. More importantlydecreasedextracellular levelsof adenosinehavebeenshownto lead toa lossof hypoxia-inducedneuroprotectionafter repeatedexposure tohypoxia [22]. Figure 1. The effects of hypoxia on adenosine release in theCNS.Hypoxia causes a breakdown of extracellular ATP and AMP along with activation of membrane-bound transporters such as ectonucleotidases, leadingtoabuild-upofextracellularadenosine.Adenosinebindspresynaptically toA1Rsattenuatingvoltagedependentcalciumchannel (VDCC)functionandthusneurotransmitter release and also binds postsynaptically to A1Rs receptors inactivating glutamatergic NMDARs. Adenosine is releasedfromastrocytes inresponse tochronichypoxia. Thedepressionofsynaptictransmissioninlongertermhypoxiagoesbeyondaneuroprotectiverole. Forexampleduringlongerdurationhypoxia,nicotinamideadeninedinucleotidephosphate-oxidase oxidaseproductionofreactiveoxygenspecies (ROS)suchassuperoxidesbymicroglialcomplement receptor3canactivateproteinphosphatase2A(PP2A),whichcauses the internalizationofpostsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacidreceptors (AMPARs) throughserine-threonine dephosphorlation[23]. This issimilar to thediscoverythat theoxygensensingC-elegansprotein egl-9, whichregulatesHIF inanoxygen-dependentmannercanalsoregulateC. elegansglutamatereceptor-1 (GLR-1) trafficking through the generation of isoform-specific transgeneswhich interactwith the GLR-1promoter [24,25]. Innormoxicconditions,egl-9binds toLin-10preventing itsphosphorylation, this complex thenallows for themovementof glutamate receptors to the synapse. Underhypoxic conditions, Lin-10 isphosphorylated, thuspreventing the formationof theEGL9/Lin-10 complex leadingtoa lackofsynapticGluR1receptors [26]. Oneparticular formofhypoxia, chronic intermittenthypoxia(CIH)mayhavespecificdetrimental effects onCNS function. CIHcan lead to theover-activationofNMDARs, leading to anoverload of intracellularCa2+ andadephosphorylationof extracellular signal-regulatedkinases (ERK) [27]. TheCA1 region of the hippocampus is thought to be selectively vulnerable toCIHdamage due to the highdensity of glutamate receptors located on its pyramidal neurons [28]. CIHalso leads 31