Nöronal Plastisite ve Nörodejeneratif Hastalıklarda NF-κB’nin Rolü

Year 2017, Volume: 7 Issue: 13, 71 - 85, 01.06.2017

Elif Nuran Yağmur Nazım Yıldız Serkan Adıgüzel Banu Femir Seray Şenyer Melis Şen Erdem Tüzün , Cem İsmail Küçükali

Abstract

NF-κB yirminci yüzyılın sonlarında açığa çıkarılmış bir transkripsiyon faktörüdür. Başlarda immün

hücrelerde varlığı gösterilirken ilerleyen çalışmalarda organizmadaki hemen hemen bütün hücrelerde

mevcut bulunduğu ortaya konulmuştur. 500’e yakın genin aktivasyonunda yer alan NF-κB immün cevap

süreci, hücre döngüsü, sağkalımı, proliferasyonu ve gelişiminin yanı sıra plastisite ve bellek oluşumu

gibi mekanizmalarda da etkinlik göstermektedir. Merkezi sinir sisteminde (MSS) NF-κB uzun

süreli potansiyasyon (long-term potentiation-LTP) sağlanmasında etkinliği ile plastisiteyi ve

dolayısıyla bellek oluşumunu etkilemektedir. Bunlara ek olarak, nörodejenerasyonun üzerinde

inflamasyonun etkisinin önemine dair çalışmalar son yıllarda artış göstermiştir. İnflamasyonun kilit

mekanizmalarının bazılarında NF-κB merkezi rol oynamaktadır. Çalışmamızda plastisite ve bellek

oluşum mekanizmalarına ek olarak, nörodejeneratif seyir izleyen Huntington hastalığı (HH),

Parkinson hastalığı (PH), Alzheimer hastalığı (AH) ve Multiple Skleroz (MS) hastalıklarının

patogenezinde NF-κB’nin etkileri incelenmiştir. Nöronal plastisite ve belirtilen hastalıkların

mekanizması ve patogenezinin NF-κB ile olan ilişkisine dair literatürdeki veriler taranmış ve

toparlanmıştır.

Keywords

NF-κB, nöronal plastisite, Nörodejeneratif hastalıklar

THE ROLE OF NF-κB IN NEURONAL PLASTICITY AND NEURODEGENERATIVE DISEASES

Abstract

NF-κB is a transcription factor emerged by the end of 20th century. At the beginning, NF-κB was

found to be present in immune cells but following studies showed its presence in almost all cells in

an organism. NF-κB takes part in the activation of almost 500 genes and have roles in mechanisms

including immune response, cell cycle, cell survival, cell proliferation and development, as well as

plasticity and memory formation. Long-term potentiation (LTP) of NF-κB in the central nervous

system (CNS) affects plasticity, hence memory formation. In addition to these, studies on the effects of

inflammation on neurodegeneration showed an increase in the last years. NF-κB plays a role in some

of the crucial inflammation mechanisms. In the current study, we investigated the effect of NF-κB in

pathogenesis of neurodegenerative diseases including Huntington’s Disease (HD), Parkinson’s Disease

(PD), Alzheimer’s Disease (AD) and Multiple Sclerosis (MS) in addition to the plasticity and memory

formation mechanisms. Studies in the literature on the relationship of NF-κB with neuronal plasticity,

mechanisms of diseases above and pathogenesis were scanned and collected.

Keywords

NF-κB, neuronal plasticity, neurodegenerative diseases

References

• 1. CamandolaS , Mattson M. NF-κB as a therapeutic target in neurodegenerative diseases. Expert Opin Ther Targets 2007, 11(2): 123-132. 2. Shih R, Wang , Yang . NF-kappaB Signaling Pathways in Neurological Inflammation: A Mini Review. Front Mol Neurosci 2015;. doi: 10.3389/fnmol.2015.00077. 3. Srinivasan M, Lahiri D. Significance of NF-κB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis. Expert Opin Ther Targets 2015; 19(4): 471-487. 4. Dalmızrak, A.Tank proteininin sinyal iletimindeki fonksiyonel analizi. Ege Üniversitesi/ Sağlık Bilimleri Enstitüsü, İzmir; 2008. 5. Pozniak PD, White MK, Khalili K. TNF-α/NF- κB Signaling in the CNS: Possible Connection to EPHB2. J Neuroimmune Pharmacol 2014; 9(2): 133-141. 6. Kandel ER. The molecular biology of memory storage: adialogue between genes and synapses. Science 2001; 294: 1030-1038. 7. Kaltschmidt C, Kaltschmidt B. NF-KappaB in Long-Term Memory and Structural Plasticity in the Adult Mammalian Brain. Front Mol Neurosci doi: 10.3389/fnmol.2015.00069, Nov 24,2015. 8. Albensi B, Mattson MP. Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse 2000;35: 151-159. 9. Memet S. NF-kB functions in the nervous system: From development to disease. Biochem Pharmaco 2006; 72: 1180-1195. 10. O’Mahony A, Raber J, Montano M, Foehr E, Han V, Lu SM, Kwon H, LeFevour A, hakraborty- Sett S, Greene WCN. F-κB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity. Mol Cell Biol 2006; 26: 7283-7298. 11. Romano A, Freudenthal R, Merlo E, Routtenberg A. Evolutionarily conserved role of the NF-kB transcription factor in neural plasticity and memory. Eur J Neurosci 2006; 24: 1507-1516. 12. Bracchi-Ricard V, Brambilla R, Levenson J, Hu WH, Bramwell A, Sweatt JD, Green EJ, Bethea JR.Astroglial nuclear factor-kB regulates learning and memory synaptic plasticity in female mice. J Neurochem 2008; 104: 611-623. 13. Freudenthal R, Romano A. Participation of Rel/NF-κB transcription factors in long-term memory in the crab Chasmagnathus. Brain Res 2000; 855: 274-281. 14. Bliss TVP, Lømo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 1973; 232: 331-356. 15. Kaltschmidt B, Ndiaye D, Korte M, Pothion S, Arbibe L, Prüllage M, Pfeiffer J, Lindecke A, Staiger V, Isral A, Kaltschmidt , Mmet S. NF-kB regulates spatial memory formation and synaptic plasticity through protein kinase A/CREB signaling. Mol Cell Biol 2006; 26: 2936-2946. 16. Freudenthal R, Romano A, Routtenberg A. Transcription factor NF-kappaB activation after in vivo perforant path LTP in mouse hip-pocampus. Hippocampus 2004; 14: 677-683. 17. Furukawa K, Mattson MP. The transcription factor NF-κB mediates increases in calcium currents and decreases in NMDA- and AMPA/ kainate-induced currents induced by tumor necrosis factor-α in hippocampal neurons. J Neurochem 1988; 70: 1876-1886. 18. Arancio O, Zhang HP, Chen X, et al. RAGE potentiates A beta induced perturbation of neuronal function in transgenic mice. EMBO J; 2004, 23: 4096-105. 19. Kassed A, Willing AE, Garbuzova-Davis S, Sanberg PR, Pennypacker KR. Lack of NF-B p50 exacerbates degeneration of hippocampal neurons after chemical exposure and impairs learning. Exp Neurol 2002; 176: 277- 288. 20. Katzman R, Saitoh T. Advances in Alzheimer’s disease. FASEB J 1991; 5: 278-278. 21. Taneli B, Sivrioğlu Y, Taneli T. Alzheimer diease. Gülhane Psychopharmacology Symposium. Ankara: Gülhane Military Medical Academy Printing Office; 1. Basım, 1999, p 31-80. 22. MP Mattson, MK Meffert. Roles for NF-jB in nerve cell survival, plasticity, and disease. Cell Death Differ 2006; 13: 852-860. 23. Gürvit H, Öge AE, Bahar SZ. Sinir Sisteminin Dejeneratif Hastalıkları. Demans Sendromu, Alzheimer Hastalığı ve Alzheimer dışı demanslar. Nobel Matbaacılık, İstanbul, Türkiye, 1. Baskı, 2004, pp 367-415. 24. Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-kB in Aging and Disease. Aging Dis 2011; 2(6): 449-465. 25. Rahman SM, Van Dam AM, Schultzberg M, Crisby M. High cholesterol diet results in increased expression of interleukin-6 and caspase- 1 in the brain of apolipoprotein E knockout and wild type mice. J Neuroimmunol 2005; 169: 59-67. 26. Sheng JG, Ito K, Skinner RD, Mrak RE, Rovnaghi CR, Van Eldik LJ, Griffin WS. In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiol Aging 1996; 17: 761-766. 27. Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 2005; 280: 40364-40374. 28. Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006; 12: 1005-1015. 29. Holmes C, El-Okl M, Williams AL, Cunningham C, Wilcockson D, and Perry VH. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2003; 74: 788-789. 30. Chami L, Buggia-Prevot V, Duplan E, Delprete D, Chami M, Peyron JF and CheclerF. Nuclear factor-kappaB regulates betaAPP and beta- and gamma-secretases differently at physiological and supraphysiological Abeta concentrations. J Biol Chem 2012; 287(29): 24573-24584. 31. Kassed CA, Butler TL, Navidomskis MT, Gordon MN, Morgan D and Pennypacker KR. Mice expressing human mutant presenilin-1 exhibit decreased activation of NF-kappaB p50 in hippocampal neurons after injury. Brain Res Mol Brain Res 2003; 110: 152–157. 32. Guo Q, Robinson N and Mattson MP. Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin- 1 by activation of NF-kappaB and stabilization of calcium homeostasis. J Biol Chem 1998; 273: 12341-12351. 33. Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE. NSAIDs and enantiomers of flurbiprofen target gamma- secretase and lower Abeta 42 in vivo. J Clin Invest 2003; 112: 440-449. 34. Boissiere F, Hunot S, Faucheux B, Duyckaerts , Hauw JJ, Agid Y and Hirsch E. Nuclear translocation of NF-kappaB in cholinergic neurons of patients with Alzheimer’s disease. NeuroReport 1997; 8: 2849-2852. 35. Mattson MP, Goodman Y, Luo H, Fu W and Furukawa K. Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration. J Neurosci Res 1997; 49: 681-697. 36. Barger SW, Horster D, Furukawa K, Goodman Y, Kriegelstein J and Mattson MP. Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: Evidence for involvement of a kappa B-binding factor and attenuation of peroxide and a2+ accumulation. Proc Natl Acad Sci USA 1995; 92: 9328-9332. 37. Ho GJ, Drego R, Hakimian E and Masliah E. Mechanisms of cell signaling and inflammation in Alzheimer’s disease. Curr Drug Targets Inflamm Allergy 2005; 4: 247-256. 38. Akama KT, Albanese C, Pestell RG, Van Eldik LJ. Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NFkappaB-dependent mechanism. Proc Natl Acad Sci USA 1998; 95: 5795-5800. 39. Lee SC, Brosnan CF. Cytokine Regulation of iNOS Expression in Human Glial Cells. Methods 1996; 10: 31-37. 40. Barger SW, Mattson MP. Induction of neuroprotective kappa B-dependent transcription by secreted forms of the Alzheimer’s beta-amyloid precursor. Brain Res Mol Brain Res 1996; 40: 116-126. 41. Strickland D, Bertoni JM. Parkinson’s prevalence estimated by a state registry. Movement Disorders 2004; 19(3) : 318-323. 42. Gaki GS, Papavassiliou AP. Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson’s disease. Neuromolecular Med 2014; 16(2): 217-230. 43. Graybiel AM. The basal ganglia: Learning new tricks and loving it. Curr Opin Neuro-biol 2005; 15(6): 638-644. 44. Wakabayashi K1, Tanji K, Mori F, Takahashi H. The Lewy body in Parkinson’s disease: Molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology 2007; 27(5): 494-506. 45. Yacoubian TA, Standaert DG. Targets for neuroprotection in Parkinson’s disease. Biochim Biophys Acta 2009; 1792(7): 676-687. 46. Amer AA, Baltimore D. An essential role for NF-kB in preventing TNF-alpha-induced cell death. Science 1996; 274(5288): 782-784. 47. Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite effects on activation of NF-kB and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 1993; 12: 2005-2015. 48. Laflamme N, Rivest S. Effects of systemic immunogenic insults and circulating proinflammatory cytokines on the transcription of the inhibitory factor kappaB alpha within specific cellular populations of the rat brain. J Neurochem 1999; 73: 309-321. 49. Yu ZF, Zhou D, heng G, Mattson MP. Neuroprotective role for the p50 subunit of NF-kB in a mouse model of Huntington’s disease. J. Mol Neurosci 2000; 15: 31-44. 50. Akundi RS, Huang Z, Eason J, Pandya JD, Zhi L, Cass WA, Sullivan PG, Büeler H. Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS ONE, doi: 10.1371/journal. pone.0016038, Jan 13, 2011. 51. Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer 2009; 9(11): 798-809. 52. Sha D, hin LS, Li L. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NFkB signaling. Hum Mol Genet 2010; 19(2): 352-363. 53. Mele A, ervantes JR, hien V, Friedman D, Ferran . Single nucleotide polymorphisms at the TNFAIP3/A20 locus and susceptibility/resistance to inflammatory and autoimmune diseases. Adv Exp Med Biol 2014; 809: 163-183. 54. Lee EG, Boone DL, hai S, Libby SL, hien M, Lodolce JP, Ma A. Failure to regulate TNFinduced NF-κB and cell death responses in A20-deficient mice. Science 2000; 289: 2350- 2354. 55. Perga S, Martire S, Montarolo F, Navone ND, alvo A, Fuda G, Marchet A, Leotta D, hi A, Bertolotto A. A20 in Multiple Sclerosis and Parkinson’s Disease: lue to a ommon Dysregulation of Anti-Inflammatory Pathways. Neurotox Res 2017; 32: 1-7. 56. Tóbon-Velasco JC, Cuevas E, Torres-Ramos MA. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) 2014; 13 (9): 1615-1626. 57. Bakris GL, Bank AJ, Kass DA, Neutel JM, Preston RA, Oparil S. Advanced glycation endproduct cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process. Am J Hypertens 2004; 17: 23S-30S. 58. Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, Luddy JS, Lue LF, Walker DG, Roher A, But84 tini M, Mucke L, Li W, Schmidt AM, Kindy M, Hyslop PA, Stern DM, Du Yan SS. RAGE potentiates Aβ-induced perturbation of neuronal function in transgenic mice. EMBO J 2004; 23: 4096-4105. 59. Cuevas E, Lantz S, Newport G, Divine B, Wu Q, Paule MG, Tobón-Velasco JC, Ali SF, Santamaría A. On the early toxic effect of quinolinic acid: involvement of RAGE. Neurosci Lett 2010; 474(2): 74-78. 60. Lee D, Park CW, Paik SR, Choi KY. The modification of α -synuclein by dicarbonyl compounds inhibits its fibril-forming process. Biochim Biophys Acta 2009; 1794: 421-30. 61. May MJ, Marienfeld RB, Ghosh S. haracterization of the IκB-kinase NEMO binding domain. J Biol Chem 2002; 277(48): 45992– 46000. 62. Flood PM, Qian L, Peterson LJ, Zhang F, Shi JS, Gao HM, Hong JS. Transcriptional Factor NF-κB as a Target for Therapy in Parkinson’s Disease. doi: 10.4061/2011/216298, Mar 30, 2011. 63. Tsuneya I, Gendelman H. Neuroimmune pharmacology. Springer. Berlin, Germany 2017; pp 89-104. 64. Paulsen JS. Cognitive impairment in Huntington disease: diagnosis and treatment. Curr Neurol Neurosci Rep 2011; 11: 474–483. 65. Gusella JF, Wexler NS, onneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins P, Ottina K, Wallace MR, Sakaguchi AY. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 1983; 306: 234-238. 66. Group THsDCR. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993; 72: 971-983. 67. Aylward EH. Magnetic resonance imaging striatal volumes: a biomarker for clinical trials in Huntington’s disease. Mov Disord 2014; 29: 1429-1433. 68. Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, Cattaneo E, Gage FH, Cleveland DW, Glass CK. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci 2014: 17: 513-521. 69. Sharp AH, Loev SJ, Schilling G, Li S-H, Li X-J, Bao J, Wagster MV, Kotzuk JA, Steiner JP, Lo A, Hedreen J, Sisodia S, Snyder SH, Dawson TM, Ryugo DK, Ross CA. Widespread expression of Huntington’s disease gene (IT15) protein product. Neuron 1995; 14: 1065-1074. 70. Caviston JP, Zajac AL, Tokito M, Holzbaur EL. Huntingtin coordinates the dynein-mediated dynamic positioning of endosomes and lysosomes. Mol Biol Cell 2011; 22(4): 478-492. 71. Träger U, Andre R, Lahiri N, Magnusson-Lind A, Weiss A, Grueninger S, McKinnon C, Sirinathsinghji E, Kahlon S, Pfister EL, Moser R, Hummerich H, Antoniou M, Bates GP, Luthi- Carter R, Lowdell MW, Björkqvist M, Ostroff GR, Aronin N, Tabrizi SJ. HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFkB pathway dysregulation. Brain 2014; 137: 819-833. 72. Takano, Hiroki, and James F. Gusella. The predominantly HEAT-like motif structure of huntingtin and its association and coincident nuclear entry with dorsal, an NF-kB/Rel/dorsal family transcription factor. BMC neuroscience 2002; 3: 15. 73. Marcora E, Kennedy MB. The Huntington’s disease mutation impairs Huntingtin’s role in the transport of NF-kB from the synapse to the nucleus. Hum Mol Genet 2010; 19: 4373- 4384. 74. Khoshnan A, Ko J, Tescu S, Brundin P, Patterson PH. IKKα and IKKβ regulation of DNA damage- induced cleavage of Huntingtin. PLoS One doi:10.1371/journal.pone.0005768, Jun 2, 2009. 75. Godavarthi SK, Narender D, Mishra A, Goswami A, Rao SNR, Nukina N, Jana NR Induction of chemokines, MCP-1, and KC in the mutant huntingtin expressing neuronal cells because of proteasomal dysfunction. J Neurochem 2009; 108: 787-795. 76. Lin B, Williams-Skipp C, Tao Y, Schleicher MS, Cano LL, Duke RC, Scheinman RI. NF-kB functions as both a proapoptotic and antiapoptotic regulatory factor within a single cell type. Cell Death Differ 1999; 6: 570-582. 77. Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D. NF-kB functions in synaptic signaling and behavior. Nat Neurosci 2003; 6: 1072–1078. doi:10.1038/nn1110 78. Kwan W, Träger U, Davalos D, Chou A, Bouchard J, Andre R, Miller A, Weiss A, Giorgini F, Cheah C, Möller T, Stella N, Akassoglou K, Tabrizi SJ, Muchowski PJ. Mutant huntingtin impairs immune cell migration in Huntington disease. J Clin Invest 2012; 122: 4737-4747. 79. Hsiao H-Y, Chen Y-C, Chen H-M, Tu P-H, Chern Y. A critical role of astrocyte-mediated nuclear factor-kB-dependent inflammation in Huntington’s disease. Hum Mol Genet 2013; 22: 1826-1842. 80. Napolitano M, Zei D, Centonze D, Palermo R, Bernardi G, Vacca A, Calabresi P, Gulino A. NF-kB/NOS cross-talk induced by mitochondrial complex II inhibition: implications for Huntington’s disease. Neurosci Lett 2008; 434: 241-246. 81. Kaltschmidt B, Kaltschmidt C. NF-kappaB in the nervous system. Cold Spring Harb doi: 10.1101/cshperspect.a001271, Sep 1, 2009. 82. Nylander A, Hafler DA. Multiple Sclerosis. J Clin Invest 2012; 122: 1180-1188. 83. Goverman J. Autoimmune T cells responses in the central nervous system. Nat Rev Immunol 2009; 9: 393-407. 84. Gveric D, Kaltschmidt C, Cuzner ML, Newcombe J. Transcription factor NF-kappaB and inhibtor I kappaBalpha are localized in macrophages in active multiple sclerosis lesions. J Neuropathol Exp Neurol 1998; 57: 168-178. 85. Lock C, Hermans G, Pedotti R, Brendolan A, , Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 2002; 8: 500- 508. 86. Mycko MP, Papoian R, Boschert U, Raine CS, Selmaj KW. cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity. Brain 2003; 126: 1048-1057. 87. Kaileh M, Sen R. NF-kappaB function in B lymphocytes, Immunol Rev 2012; 246; 254- 271. 88. Zheng Y, Vig M, Lyons J, van Parijs L, Beg AA. Combined deficiency of p50 and cRel in CD4+ T cells revelas an essential requirement for nuclear factor kB in regulating mature T cell survival and in vivo function. J Exp Med 2003; 197(7): 861-874. 89. Köntgen F, Grumont RJ, Strasser A, Metcalf D, Li R, Tarlington D, Gerondakis S. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte profileration, humoral immunity, and interleukin-2 expression. Genes Dev 1995; 9(16): 1965-1977. 90. Hilliard BA, Mason N, Xu L, Sun J, Lamhamedi- Cherradi SE, Liou HC, Hunter C, Chen YH. Critical roles of c-Rel in autoimmune inflammation and helper T cell differentiation. J Clin Invest 2002; 110 (6): 843-850. 91. McGaugh, J.L. Memory-a century of consolidation. Science 2000; 287: 248-251. 92. Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D. NF-k B functions in synaptic signaling and behavior. Nat Neurosci 2003; 6: 1072-1078.