Analyses of fear memory in Arc/Arg3.1-deficient mice: intact short-term memory and impaired long-term and remote memory


Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) was originally identified in patients with seizures. It is densely distributed in the hip-pocampus and amygdala in particular. Because the expression of Arc/Arg3.1 is regulated by nerve in-puts, it is thought to be an immediate early gene. As shown both in vitro and in vivo, Arc/Arg3.1 is in-volved in synaptic consolidation and regulates some forms of learning and memory in rats and mice [1,2]. Furthermore, a recent study suggests that Arc/Arg3.1 may play a significant role in signal transmission via AMPA-type glutamate receptors [3-5]. Therefore, we conducted a detailed analysis of fear memory in Arc/Arg3.1-deficient mice. As previously reported, the knockout animals exhib-ited impaired fear memory in both contextual and cued test situations. Although Arc/Arg3.1-deficient mice showed almost the same performance as wild-type littermates 4 hr after a conditioning trial, their performance was impaired in the retention test after 24 hr or longer, either with or without reconsolidation. Immunohistochemical analyses showed an abnormal density of GluR1 in the hip-pocampus of Arc/Arg3.1-deficient mice; however, an application of AMPA potentiator did not improve memory performance in the mutant mice. Memory impairment in Arc/Arg3.1-deficient mice is so ro-bust that the mice provide a useful tool for devel-oping treatments for memory impairment.

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Yamada, K. , Homma, C. , Tanemura, K. , Ikeda, T. , Itohara, S. and Nagaoka, Y. (2011) Analyses of fear memory in Arc/Arg3.1-deficient mice: intact short-term memory and impaired long-term and remote memory. World Journal of Neuroscience, 1, 1-8. doi: 10.4236/wjns.2011.11001.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Guzowski, J., Lyford, G., Stevenson, G., et al. (2000) In- hibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. The Journal of Neuroscience, 20, 3993-4001.
[2] Plath, N., Ohana, O., Dammermann, B., et al. (2006) Arc/ Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron, 52, 437-444. doi:10.1016/j.neuron.2006.08.024
[3] Chowdhury, S., Shepherd, J.D., Okuno, H., et al. (2006) Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron, 52, 445- 459. doi:10.1016/j.neuron.2006.08.033
[4] Rial Verde, E.M., Lee-Osbourne, J., Worley, P.F., et al. (2006) Increased expression of the immediate-early gene Arc/Arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron, 52, 461-474. doi:10.1016/j.neuron.2006.09.031
[5] Shepherd, J.D., Rumbaugh, G., Wu, J., Chowdhury, S., et al. (2006) Arc/Arg3.1 mediates homeostatic synaptic sca- ling of AMPA receptors. Neuron, 52, 475-484. doi:10.1016/j.neuron.2006.08.034
[6] Steward, O. and Worley, P. (2002) Local synthesis of pro- teins at synaptic sites on dendrites: role in synaptic plasticity and memory consolidation? Neurobiology of Lear- ning and Memory, 78, 508-527. doi:10.1006/nlme.2002.4102
[7] Lyford, G., Yamagata, K., Kaufmann, W., et al. (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron, 14, 433-445. doi:10.1016/0896-6273(95)90299-6
[8] Rodríguez, J.J., Davies, H.A., Silva, A.T., et al. (2005) Long-term potentiation in the rat dentate gyrus is associated with enhanced Arc/Arg3.1 protein expression in spines, dendrites and glia. European Journal of Neuroscience, 21, 2384-2396. doi:10.1111/j.1460-9568.2005.04068.x
[9] Steward, O. and Worley, P. (2001) A cellular mechanism for targeting newly synthesized mRNAs to synaptic sites on dendrites. Proceedings of the National Academy of Sciences of the United States of America, 98, 7062-7068. doi:10.1073/pnas.131146398
[10] Fosnaugh, J., Bhat, R., Yamagata, K., et al. (1995) Activation of arc, a putative “effector” immediate early gene, by cocaine in rat brain. Journal of Neurochemistry, 64, 2377-2380. doi:10.1046/j.1471-4159.1995.64052377.x
[11] Kodama, M., Akiyama, K., Ujike, H., et al. (1998) A robust increase in expression of arc gene, an effector immediate early gene, in the rat brain after acute and chronic methamphetamine administration. Brain Research, 796, 273-283. doi:10.1016/S0006-8993(98)00349-7
[12] Moro, H., Sato, H., Ida, I., et al. (2007) Effects of SKF- -38393, a dopamine D1 receptor agonist on expression of amphetamine-induced behavioral sensitization and expression of immediate early gene arc in prefrontal cortex of rats. Pharmacology Biochemistry and Behavior, 87, 56-64. doi:10.1016/j.pbb.2007.03.020
[13] Yamagata, K., Suzuki, K., Sugiura, H., et al. (2000) Activation of an effector immediate-early gene arc by methamphetamine. Annals of the New York Academy of Sci- ences, 914, 22-32. doi:10.1111/j.1749-6632.2000.tb05180.x
[14] Nakahara, T., Kuroki, T., Hashimoto, K., et al. (2000) Effect of atypical antipsychotics on phencyclidine-in- du- ced expression of arc in rat brain. NeuroReport, 11, 551-555. doi:10.1097/00001756-200002280-00025
[15] Kremerskothen, J., Wendholt, D., Teber, I., et al. (2002) Insulin-inducedexpression of the activity-regulated cyto- skeleton-associated gene (ARC) in human neuroblastoma cells requires p21(ras), mitogen-activated protein kinase/ extracellular regulated kinase and src tyrosine kinases but is protein kinase C-independent. Neuroscience Letters, 22, 153-156.
[16] Kunizuka, H., Kinouchi, H., Arai, S., et al. (1999) Activation of arc gene, a dendritic immediate early gene, by middle cerebral artery occlusion in rat brain. NeuroReport, 10, 1717-1722. doi:10.1097/00001756-199906030-00017
[17] Larsen, M.H., Olesen, M., Woldbye, D.P., et al. (2005) Regulation of activity-regulated cytoskeleton protein (arc) mRNA after acute and chronic electroconvulsive stimulation in the rat. Brain Research, 1064, 161-165. doi:10.1016/j.brainres.2005.09.039
[18] Mikkelsen, J.D. and Larsen, M.H. (2006) Effects of stre- ss and adrenalectomy on activity-regulated cytoskeleton protein (arc) gene expression. Neuroscience Letters, 403, 239-243. doi:10.1016/j.neulet.2006.04.040
[19] Guthrie, K., Rayhanabad, J., Kuhl, D., et al. (2000) Odors regulate Arc expression in neuronal ensembles en- gaged in odor processing. NeuroReport, 11, 1809-1813. doi:10.1097/00001756-200006260-00003
[20] Matsuoka, M., Yamagata, K., Sugiura, H., et al. (2002) Expression and regulation of the immediate-early gene product Arc in the accessory olfactory bulb after mating in male rat. Neuroscience, 11, 251-258.
[21] Montag-Sallaz, M. and Montag, D. (2003) Learning- induced arg 3.1/arc mRNA expression in the mouse brain. Learning and Memory, 10, 99-107. doi:10.1101/lm.53403
[22] Kelly, M.P. and Deadwyler, S.A. (2003) Experience- dependent regulation of the immediate-early gene arc differs across brain regions. The Journal of Neuroscience, 23, 6443-6451.
[23] Taishi, P., Sanchez, C., Wang, Y., et al. (2001) Conditions that affect sleep alter the expression of molecules associated with synaptic plasticity. American Journal of Physiology: Regulatory Integrative and Comparative Physiology, 281, R839-R845.
[24] Kelly, M.P. and Deadwyler, S.A. (2002) Acquisition of a novel behavior induces higher levels of arc mRNA than does overtrained performance. Neuroscience, 110, 617- 626. doi:10.1016/S0306-4522(01)00605-4
[25] Ons, S., Martí, O. and Armario, A. (2004) Stress-induced activation of the immediate early gene Arc (activity-re- gulated cytoskeleton-associated protein) is restricted to telencephalic areas in the rat brain: relationship to c-fos mRNA. Journal of Neurochemistry, 89, 1111-1118. doi:10.1111/j.1471-4159.2004.02396.x
[26] Cook, E.H., Jr., Lindgren, V., Leventhal, B.L., et al. (1997) Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. The American Journal of Human Genetics, 60, 928-934.
[27] Glessner, J.T., Wang, K., Cai, G., Korvatsuka, O., et al. (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature, 459, 569- 573. doi:10.1038/nature07953
[28] Suteliffe, J.S., Nurmi, E.L. and Lombroso, P.J. (2003) Genetics of childhood disorders: XLVII. Autism, part 6: duplication and inherited susceptibility of chromosome 15q11-q13 genes in autism. Journal of the American Ac- ademy of Child and Adolescent Psychiatry, 42, 253-256. doi:10.1097/00004583-200302000-00021
[29] Kishino, T., Lalande, M. and Wagstaff, J. (1997) UBE3A/ E6-AP mutations cause Angeleman syndrome. Nature Ge- netics, 15, 70-73. doi:10.1038/ng0197-70
[30] Matsuura, T., Sutcliffe, J. S., Fang, P., et al. (1997) De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genetics, 15, 74-77. doi:10.1038/ng0197-74
[31] Greer, P.L., Hanayama, R., Bloodgood, B.L., et al. (2010) The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell, 140, 704- 716. doi:10.1016/j.cell.2010.01.026
[32] Radulovic, J., Kammermeir, J. and Spiess, J. (1998) Generalization of fear responses in C57BL/6J mice subjec- ted to one-trial foreground contextual fear conditioning. Behavioral Brain Research, 95, 179-189. doi:10.1016/S0166-4328(98)00039-4
[33] Suzuki, A., Josselyn, S.A., Frankland, P.W., et al. (2004) Memory reconsolidation and extinction have distinct temporal and biochemical signatures. The Journal of Neuroscience, 24, 4787-4795. doi:10.1523/JNEUROSCI.5491-03.2004
[34] LeDoux, J. (1993) Emotional memory: in search of systems and synapses. Annals of the New York Academy of Sciences, 702, 149-157. doi:10.1111/j.1749-6632.1993.tb17246.x
[35] von Hertzen, L.S.J. and Giese, K.P. (2005) Memory reconsolidation engages only a subset of immediate-early genes induced during consolidation. The Journal of Neuro- science, 25, 1935-1942.
[36] MacDonald, J.F., Jackson, M.F. and Beazely, M.A. (2006) Hippocampal long-term synaptic plasticity and signal am- plification of NMDA receptors. Critical Reviews in Neurobiology, 18, 71-84.
[37] Sekiguchi, M., Yamada, K., Jin, J., et al. (2001) The AMPA receptor allosteric potentiator, PEPA ameliorates post-ischemic memory impairment. NeuroReport, 12, 2947- 2950. doi:10.1097/00001756-200109170-00038
[38] Yamada, D., Zushida, K., Wada, K., et al. (2009) Pharmacological discrimination of extinction and reconsolidation of contextual fear memory by a potentiator of AMPA receptors. Neuropsychopharmacology, 34, 2574- 2584. doi:10.1038/npp.2009.86
[39] Tanemura, K., Igarashi, K., Matsugami, T.-R., et al. (2009) Intraurine environment-genome interaction and children’s development (2): EBrain structure impairment and behavioral disturbance induced in male mice offspring by a single intraperitoneal administration of domoic acid (DA) to their dams. The Journal of Toxicological Sci- ences, 34, 279-286. doi:10.2131/jts.34.SP279

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