Seite - 11 - in Advances in Neuroimmunology

BrainSci. 2016,6, 19 in thehippocampusof IL-6 tgmicecouldaffect synaptic function. STAT3hasbeenshowntobehighly expressed inCNSneurons,where it ispresent in thepostsynapticdensity,andtoregulatesynaptic plasticity (LTD) in thehippocampus[1]. Inadditionto increased levelsofGFAPandSTAT3, reduced levels ofGAD65/67, the synthetic enzyme for the inhibitory transmitterGABA,wereobserved in the IL-6 tghippocampus[60], consistentwith the immunohistochemical studies indicatinganegative effectof theelevated levelsof IL-6onthestructureof inhibitory interneurons [49,54]. Comparedto thehippocampusfromnon-tgmice, thehippocampusfromCCL2-tgmiceshowed elevated levels of synapsin 1, a presynaptic protein involved in transmitter release, andGluN1, the essential subunit ofNMDAreceptors [58,67]. NMDAreceptorsplaya critical role inneuronal development, synapticplasticity,andneuronal toxicity,andarean important targetsite for therapeutic intervention inanumberofneurologicaldisorders [81,82]. Theneuroadaptivechanges insynapsin1 andGluN1levelswerenotevident in theCCL2-tgSJLhippocampus,where theonlychangeswere an increase inCD11bandGFAP[61]. Takentogether, theseresults showthatneuroadaptivechanges occur at the level of synaptic proteins in the IL-6 tg andCCL2-tg hippocampus. The differences inproteins targeted in the IL-6 tgandCCL2-tghippocampuscouldcontribute todifferences in the synapticpropertiesaltered in the twotransgenic lines. 7.BehavioralStudies Alterations in synaptic function can result in changes in behavior. Twobehavioral tests that evaluate the functioningof thehippocampusare theavoidance learningtestandthecontextual fear conditioningtest. Thesebehavioral testswereusedexaminehippocampal function intheIL-6 tgor CCL2-tg lines. Behaviorhasnotbeentested intheCXCL10-tg line. TheIL-6 tgmicedidnotshowa behavioraldeficit comparedtonon-tgmice in theavoidance learningwhentestedat3monthsofage. However, by6monthsofage the IL-6 tgmiceexhibitedasignificantdeficit in their ability to learn theavoidance response,whichdeclined furtherby12monthsof age [54]. TheCCL2-tgmicewere examined inbehavioral tests for contextual fear conditioningat2–3monthsofage. Therewereno significantdifferencesbetweentheCCL2-tgandnon-tgmice in these tests [67]. Theseresults suggest the lackof significanthippocampaldysfunctionat3monthsofage inboth the IL-6 tgandCCL2tg mice,at leastunderbaselineconditions in these tests. 8.CovertNeuroadaptiveChanges Taken together, studiesof synaptic functionandproteinexpression in thehippocampus from IL-6 tgandCCL2-tgmicerevealedrelatively fewneuroadaptivechangesproducedbytherespective neuroimmunefactorunderbaselineconditions, althoughtheobservedchangescouldsignificantly alterCNS functiondependingonphysiological or pathological context. However, studies on the effectsofacutealcoholonsynaptic function in thehippocampusfromIL-6 tgandCCL2-tgmiceand their respectivenon-tg controls revealed covert neuroadaptive changes that resulted in analtered the response toalcohol (Table4). For example, although therewasnodifference in themagnitude ofPTPandLTP inhippocampal slices from IL-6 tgorCCL2-tgmice compared to their respective non-tgcontrolsunderbaselineconditions, exposure toacutealcohol (60mM)depressedPTPandLTP inhippocampal slices fromnon-tgmice fromboth the IL-6andCCL-2 lines,whilePTPandLTPin hippocampalslices fromtheIL-6 tgandCCL2-tghippocampuswereresistant to thiseffectofacute alcohol [67,70]. Thus, thehippocampusfromtheIL-6 tgandCCL2-tgmiceshowedasimilar resistance to thedepressingeffectsofalcoholonLTPandPTP.Differences in theresponse toalcoholwerealso observedbetweenIL-6 tgandCCL2-tgmice in theeffectsofalcoholonthe fEPSPandPS.Forexample, 60mMacute alcohol reduced the fEPSPandPS inhippocampal slices fromnon-tgmice from the IL-6andCCL2 linesand inhippocampal slices fromCCL2-tgmice,whereas inhippocampal slices fromIL-6 tgmice the samedoseofalcohol increased the fEPSPandPS [67,70]. 60mMalcohol is a pharmacologicallyrelevantdose thatwouldproducesevere intoxication inhumans. 11