Page - 13 - in Advances in Neuroimmunology

BrainSci. 2016,6, 19 the involvement of a specific neuroimmune factor inCNSdevelopment, function or dysfunction. Onecaveat to thesemodels is thatexpression in the transgenicmodelor lackofexpression in theKO modeloccursover the lifespanof theanimal,whichcould influenceCNSdevelopment. It isunclear iforhowpotentialdevelopmenteffectswould impactstudies inadultanimals.However,emerging researchontheactionsofneuroimmunefactorsonCNSdevelopment is starting toprovideanswers to thisquestion. Overall, the studies of synaptic function in the hippocampus from the three transgenic lines revealedrelatively fewalterations. This result is consistentwith therelative lackofneuropathology in thehippocampusof the transgenicmiceat theagesstudied,andraises thepossibility thatadditional factorsmaybenecessarywhenpathology isobserved. Bothsimilaritiesanddifferenceswereobserved in theeffectsof the threeneuroimmunefactorsonsynaptic function, suggestingthatsimilaritiesand differences exist in underlyingmechanisms, and are likely to be reflected in the consequences of elevatedexpressionunderdifferentpathological contexts. Althoughonlya limitednumberofneuroadaptivechanges insynaptic functionwere identified under basal conditions, several experimental manipulations revealed that covert neuroadaptive changes were produced by elevated expression of the neuroimmune factors. These covert neuroadaptivechangesmayhavebeenresponsible for theapparentnormalizationof functionunder baselineconditionssuch thatgenotypicdifferenceswerenotobserved. The identificationofcovert actions illustrates the importance of physiological or pathological context in the consequence of cytokine or chemokine actions in theCNS.Both the identifiedand covert neuroadaptive changes resultingfromincreasedastrocyteproductionoftheneuroimmunefactorscouldcontributetocognitive impairment inapathological context. Themechanismsandmolecular targetsunderlying theneuroadaptivechangesproducedbyIL-6, CCL2,andCXCL10haveyet tobeelucidated. Studies toaddress these issuesarean important future direction,andareessential foramorecompleteunderstandingof theactionsandrolesof IL-6,CCL2 andCXCL10inCNSphysiologyandpathology. Thelevelofexpression,durationofexposure,presence ofotherneuroimmunefactors, andbiological contextareall likely tobe importantvariables, andtheir biological impactwill alsoneed tobe resolved in future studies. Taken together, such information couldrevealnewtargets for therapeutic intervention forarangeofpathophysiological conditions that areassociatedwith increasedexpressionof IL-6,CCL2and/orCXCL10 in theCNS. Acknowledgments:SupportedbyNIAAAGrantAA019261. Conflictsof Interest:Theauthordeclaresnoconflictof interest. References 1. Nicolas, C.S.; Peineau, S.; Amici, M.; Csaba, Z.; Fafouri, A.; Javalet, C.; Collett, V.J.; Hildebrandt, L.; Seaton,G.; Choi, S.L.; et al. The JAK/STATpathway is involved in synaptic plasticity. Neuron 2012, 73, 374–390. [CrossRef] [PubMed] 2. Zheng,C.;Zhou,X.W.;Wang, J.Z.Thedualrolesofcytokines inAlzheimer’sdisease:Updateoninterleukins, TNF-α,TGF-βandIFN-γ.Transl.Neurodegener. 2016. [CrossRef] [PubMed] 3. De Vries, E.E.; van denMunckhof, B.; Braun, K.P.; van Royen-Kerkhof, A.; de Jager,W.; Jansen, F.E. Inflammatorymediators inhumanepilepsy:Asystematic reviewandmeta-analysis.Neurosci. Biobehav. Rev. 2016,63, 177–190. [CrossRef] [PubMed] 4. Rothhammer, V.; Quintana, F.J. Control of autoimmune CNS inflammation by astrocytes. Semin. Immunopathol. 2015,37, 625–638. [CrossRef] [PubMed] 5. Crews, F.T.; Vetreno,R.P.Neuroimmunebasis of alcoholic braindamage. Int. Rev. Neurobiol. 2014, 118, 315–357. [PubMed] 6. Drew,P.D.;Kane,C.J.Fetalalcohol spectrumdisordersandneuroimmunechanges. Int. Rev.Neurobiol. 2014, 118, 41–80. [PubMed] 7. Chastain,L.G.;Sarkar,D.K.Roleofmicroglia inregulationofethanolneurotoxicaction. Int. Rev.Neurobiol. 2014,118, 81–103. [PubMed] 13