社交壓力(social stress)被認為是多種精神性疾病的主要成因，並且是一個會使人產生自殺傾向的高度風險因子。過去的研究指出，慢性社交挫敗壓力會降低社交興趣與社交互動，但對於是由甚麼樣的機制造成此類社交行為缺陷，我們尚不清楚。近期的研究發現，腦衰蛋白反應媒介蛋白(collapsin response mediator protein, CRMP)共有五個成員(CRMP1~5)形成一個家族，它們高度表現在神經系統中，並可在神經發育過程中動態調節生長錐(growth cone)。此外，有研究指出CRMP的家族成員參與在多種精神性疾病的發病機制之中，但其中CRMP5的角色仍未清楚。因此，我們首先建立了社交挫敗模式(social defeat model)來模擬慢性社交壓力，通過西方墨點法(western blot)，我們發現相較於控制組，經歷社交挫敗的小鼠們，在海馬迴中會大量表現CRMP5。為了確認CRMP5對小鼠社交行為的影響，我們將帶有Crmp5基因的慢病毒(lentiviruses)質體打入小鼠的海馬迴中，使CRMP5能在海馬迴中過度表達(overexpression)。行為實驗發現，CRMP5過度表現的小鼠會展現出社交迴避的行為，表明CRMP5和社交行為缺陷有關。更進一步的了解CRMP5的調控機制，我們分析了成熟的腦源性神經營養因子(mature Brain-derived neurotrophic factor, mBDNF)，發現CRMP5的過度表現會提高mBDNF的表現量，說明CRMP5會藉由調控mBDNF的表現來影響小鼠的行為。歸納整體的實驗結果，我們發現海馬迴中CRMP5在情緒調節上所扮演的角色，並且可能對社交缺陷的治療上提供一個有希望的治療方法。

Social stress is viewed as a major factor in the etiology of several psychopathologies and a known risk factor for suicide attempts. Previous studies suggest that chronic social defeat stress increases deficits in social interest and social interaction. However, the mechanisms of social behavioral deficits remain unclear. Recent studies revealed that collapsin response mediator protein (CRMP) family has five members (CRMP1 to 5). They were highly expressed in the nervous system and could coordinate the dynamic regulation of growth cone during neural development. Additionally, CRMP family was reported to be associated with the pathogenesis of various neuropsychiatric disorders, but the CRMP5 still unclear. Therefore, we first established a social defeat paradigm to perform chronic social stress. By western blot analyzing, we found that defeated mice displayed higher hippocampal CRMP5 levels than control mice. We then injected Crmp5 cDNA-expressing lentiviruses into mouse hippocampus to confirm the functions of CRMP5 in social behaviors. The data showed that social avoidance behaviors were exhibited in the Crmp5 gene overexpression group, suggesting CRMP5 could prompt social deficits. To further elucidate the mechanism of CRMP5, we analyzed the expression of mature Brain-derived neurotrophic factor (mBDNF) and found that mBDNF was increased in CRMP5 overexpression group, implying mBDNF regulated the mice behavior by following the expression of CRMP5. Taken together, we disclosure the role of hippocampal CRMP5 in regulating emotional regulation and may provide a promising therapeutic approach in social deficits.

Arimura, N., Menager, C., Fukata, Y., & Kaibuchi, K. (2004). Role of CRMP-2 in neuronal polarity. J Neurobiol, 58(1), 34-47. doi:10.1002/neu.10269
Arimura, N., Menager, C., Kawano, Y., Yoshimura, T., Kawabata, S., Hattori, A., . . . Kaibuchi, K. (2005). Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol, 25(22), 9973-9984. doi:10.1128/mcb.25.22.9973-9984.2005
Bader, V., Tomppo, L., Trossbach, S. V., Bradshaw, N. J., Prikulis, I., Leliveld, S. R., . . . Korth, C. (2012). Proteomic, genomic and translational approaches identify CRMP1 for a role in schizophrenia and its underlying traits. Hum Mol Genet, 21(20), 4406-4418. doi:10.1093/hmg/dds273
Baez-Mendoza, R., & Schultz, W. (2013). The role of the striatum in social behavior. Front Neurosci, 7, 233. doi:10.3389/fnins.2013.00233
Barnabe-Heider, F., & Miller, F. D. (2003). Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci, 23(12), 5149-5160.
Beery, A. K., & Kaufer, D. (2015). Stress, social behavior, and resilience: insights from rodents. Neurobiol Stress, 1, 116-127. doi:10.1016/j.ynstr.2014.10.004
Berton, O., McClung, C. A., Dileone, R. J., Krishnan, V., Renthal, W., Russo, S. J., . . . Nestler, E. J. (2006). Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science, 311(5762), 864-868. doi:10.1126/science.1120972
Bienvenu, O. J., & Ginsburg, G. S. (2007). Prevention of anxiety disorders. Int Rev Psychiatry, 19(6), 647-654. doi:10.1080/09540260701797837
Bretin, S., Reibel, S., Charrier, E., Maus-Moatti, M., Auvergnon, N., Thevenoux, A., . . . Gauchy, C. (2005). Differential expression of CRMP1, CRMP2A, CRMP2B, and CRMP5 in axons or dendrites of distinct neurons in the mouse brain. J Comp Neurol, 486(1), 1-17. doi:10.1002/cne.20465
Brittain, J. M., Piekarz, A. D., Wang, Y., Kondo, T., Cummins, T. R., & Khanna, R. (2009). An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem, 284(45), 31375-31390. doi:10.1074/jbc.M109.009951
Brown, G. W., & Prudo, R. (1981). Psychiatric disorder in a rural and an urban population: 1. Aetiology of depression. Psychol Med, 11(3), 581-599.
Buel, G. R., Rush, J., & Ballif, B. A. (2010). Fyn promotes phosphorylation of collapsin response mediator protein 1 at tyrosine 504, a novel, isoform-specific regulatory site. J Cell Biochem, 111(1), 20-28. doi:10.1002/jcb.22659
Charrier, E., Reibel, S., Rogemond, V., Aguera, M., Thomasset, N., & Honnorat, J. (2003). Collapsin response mediator proteins (CRMPs): involvement in nervous system development and adult neurodegenerative disorders. Mol Neurobiol, 28(1), 51-64. doi:10.1385/mn:28:1:51
Cole, A. R., Causeret, F., Yadirgi, G., Hastie, C. J., McLauchlan, H., McManus, E. J., . . . Sutherland, C. (2006). Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem, 281(24), 16591-16598. doi:10.1074/jbc.M513344200
Conner, J. M., Lauterborn, J. C., Yan, Q., Gall, C. M., & Varon, S. (1997). Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci, 17(7), 2295-2313.
Fallin, M. D., Lasseter, V. K., Avramopoulos, D., Nicodemus, K. K., Wolyniec, P. S., McGrath, J. A., . . . Pulver, A. E. (2005). Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios. Am J Hum Genet, 77(6), 918-936. doi:10.1086/497703
Fukata, Y., Itoh, T. J., Kimura, T., Menager, C., Nishimura, T., Shiromizu, T., . . . Kaibuchi, K. (2002). CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol, 4(8), 583-591. doi:10.1038/ncb825
Hill, S. K., Bishop, J. R., Palumbo, D., & Sweeney, J. A. (2010). Effect of second-generation antipsychotics on cognition: current issues and future challenges. Expert Rev Neurother, 10(1), 43-57. doi:10.1586/ern.09.143
Hotta, A., Inatome, R., Yuasa-Kawada, J., Qin, Q., Yamamura, H., & Yanagi, S. (2005). Critical role of collapsin response mediator protein-associated molecule CRAM for filopodia and growth cone development in neurons. Mol Biol Cell, 16(1), 32-39. doi:10.1091/mbc.e04-08-0679
Hou, S. T., Jiang, S. X., Desbois, A., Huang, D., Kelly, J., Tessier, L., . . . Kappler, J. (2006). Calpain-cleaved collapsin response mediator protein-3 induces neuronal death after glutamate toxicity and cerebral ischemia. J Neurosci, 26(8), 2241-2249. doi:10.1523/jneurosci.4485-05.2006
Jeronimus, B. F., Kotov, R., Riese, H., & Ormel, J. (2016). Neuroticism's prospective association with mental disorders halves after adjustment for baseline symptoms and psychiatric history, but the adjusted association hardly decays with time: a meta-analysis on 59 longitudinal/prospective studies with 443 313 participants. Psychol Med, 46(14), 2883-2906. doi:10.1017/s0033291716001653
Katoh-Semba, R., Asano, T., Ueda, H., Morishita, R., Takeuchi, I. K., Inaguma, Y., & Kato, K. (2002). Riluzole enhances expression of brain-derived neurotrophic factor with consequent proliferation of granule precursor cells in the rat hippocampus. Faseb j, 16(10), 1328-1330. doi:10.1096/fj.02-0143fje
Khanna, R., Wilson, S. M., Brittain, J. M., Weimer, J., Sultana, R., Butterfield, A., & Hensley, K. (2012). Opening Pandora's jar: a primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders. Future Neurol, 7(6), 749-771. doi:10.2217/fnl.12.68
Krabbendam, L., & van Os, J. (2005). Schizophrenia and urbanicity: a major environmental influence--conditional on genetic risk. Schizophr Bull, 31(4), 795-799. doi:10.1093/schbul/sbi060
Krishnan, V., Han, M. H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., . . . Nestler, E. J. (2007). Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell, 131(2), 391-404. doi:10.1016/j.cell.2007.09.018
Leung, T., Ng, Y., Cheong, A., Ng, C. H., Tan, I., Hall, C., & Lim, L. (2002). p80 ROKalpha binding protein is a novel splice variant of CRMP-1 which associates with CRMP-2 and modulates RhoA-induced neuronal morphology. FEBS Lett, 532(3), 445-449.
Liu, W., Zhou, X. W., Liu, S., Hu, K., Wang, C., He, Q., & Li, M. (2009). Calpain-truncated CRMP-3 and -4 contribute to potassium deprivation-induced apoptosis of cerebellar granule neurons. Proteomics, 9(14), 3712-3728. doi:10.1002/pmic.200800979
Macedo, G. C., Morita, G. M., Domingues, L. P., Favoretto, C. A., Suchecki, D., & Quadros, I. M. H. (2018). Consequences of continuous social defeat stress on anxiety- and depressive-like behaviors and ethanol reward in mice. Horm Behav, 97, 154-161. doi:10.1016/j.yhbeh.2017.10.007
McCormick, C. M., Smith, C., & Mathews, I. Z. (2008). Effects of chronic social stress in adolescence on anxiety and neuroendocrine response to mild stress in male and female rats. Behav Brain Res, 187(2), 228-238. doi:10.1016/j.bbr.2007.09.005
Miczek, K. A., Covington, H. E., 3rd, Nikulina, E. M., Jr., & Hammer, R. P. (2004). Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits. Neurosci Biobehav Rev, 27(8), 787-802. doi:10.1016/j.neubiorev.2003.11.005
Mineur, Y. S., Belzung, C., & Crusio, W. E. (2006). Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice. Behav Brain Res, 175(1), 43-50. doi:10.1016/j.bbr.2006.07.029
Moutal, A., Dustrude, E. T., Largent-Milnes, T. M., Vanderah, T. W., Khanna, M., & Khanna, R. (2017). Blocking CRMP2 SUMOylation reverses neuropathic pain. Mol Psychiatry. doi:10.1038/mp.2017.117
Nagai, J., Baba, R., & Ohshima, T. (2017). CRMPs Function in Neurons and Glial Cells: Potential Therapeutic Targets for Neurodegenerative Diseases and CNS Injury. Mol Neurobiol, 54(6), 4243-4256. doi:10.1007/s12035-016-0005-1
Niisato, E., Nagai, J., Yamashita, N., Abe, T., Kiyonari, H., Goshima, Y., & Ohshima, T. (2012). CRMP4 suppresses apical dendrite bifurcation of CA1 pyramidal neurons in the mouse hippocampus. Dev Neurobiol, 72(11), 1447-1457. doi:10.1002/dneu.22007
Phillips, H. S., Hains, J. M., Armanini, M., Laramee, G. R., Johnson, S. A., & Winslow, J. W. (1991). BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron, 7(5), 695-702.
Ponnusamy, R., & Lohkamp, B. (2013). Insights into the oligomerization of CRMPs: crystal structure of human collapsin response mediator protein 5. J Neurochem, 125(6), 855-868. doi:10.1111/jnc.12188
Prigerson, H. G., Shear, M. K., Bierhals, A. J., Zonarich, D. L., & Reynolds, C. F., 3rd. (1996). Childhood adversity, attachment and personality styles as predictors of anxiety among elderly caregivers. Anxiety, 2(5), 234-241. doi:10.1002/(sici)1522-7154(1996)2:5<234::Aid-anxi5>3.0.Co;2-m
Quach, T. T., Duchemin, A. M., Rogemond, V., Aguera, M., Honnorat, J., Belin, M. F., & Kolattukudy, P. E. (2004). Involvement of collapsin response mediator proteins in the neurite extension induced by neurotrophins in dorsal root ganglion neurons. Mol Cell Neurosci, 25(3), 433-443. doi:10.1016/j.mcn.2003.11.006
Quach, T. T., Honnorat, J., Kolattukudy, P. E., Khanna, R., & Duchemin, A. M. (2015). CRMPs: critical molecules for neurite morphogenesis and neuropsychiatric diseases. Mol Psychiatry, 20(9), 1037-1045. doi:10.1038/mp.2015.77
Romanov, K., Appelberg, K., Honkasalo, M. L., & Koskenvuo, M. (1996). Recent interpersonal conflict at work and psychiatric morbidity: a prospective study of 15,530 employees aged 24-64. J Psychosom Res, 40(2), 169-176.
Rosslenbroich, V., Dai, L., Baader, S. L., Noegel, A. A., Gieselmann, V., & Kappler, J. (2005). Collapsin response mediator protein-4 regulates F-actin bundling. Exp Cell Res, 310(2), 434-444. doi:10.1016/j.yexcr.2005.08.005
Schuster, T. L., Kessler, R. C., & Aseltine, R. H., Jr. (1990). Supportive interactions, negative interactions, and depressed mood. Am J Community Psychol, 18(3), 423-438.
Sellers, R., Collishaw, S., Rice, F., Thapar, A. K., Potter, R., Mars, B., . . . Thapar, A. (2013). Risk of psychopathology in adolescent offspring of mothers with psychopathology and recurrent depression. Br J Psychiatry, 202, 108-114. doi:10.1192/bjp.bp.111.104984
Shively, C. A., Grant, K. A., Ehrenkaufer, R. L., Mach, R. H., & Nader, M. A. (1997). Social stress, depression, and brain dopamine in female cynomolgus monkeys. Ann N Y Acad Sci, 807, 574-577.
Slavich, G. M., Thornton, T., Torres, L. D., Monroe, S. M., & Gotlib, I. H. (2009). TARGETED REJECTION PREDICTS HASTENED ONSET OF MAJOR DEPRESSION. J Soc Clin Psychol, 28(2), 223-243. doi:10.1521/jscp.2009.28.2.223
Tabares-Seisdedos, R., & Rubenstein, J. L. (2009). Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer. Mol Psychiatry, 14(6), 563-589. doi:10.1038/mp.2009.2
Uchida, Y., Ohshima, T., Sasaki, Y., Suzuki, H., Yanai, S., Yamashita, N., . . . Goshima, Y. (2005). Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes Cells, 10(2), 165-179. doi:10.1111/j.1365-2443.2005.00827.x
Uchida, Y., Ohshima, T., Yamashita, N., Ogawara, M., Sasaki, Y., Nakamura, F., & Goshima, Y. (2009). Semaphorin3A signaling mediated by Fyn-dependent tyrosine phosphorylation of collapsin response mediator protein 2 at tyrosine 32. J Biol Chem, 284(40), 27393-27401. doi:10.1074/jbc.M109.000240
van Boxelaere, M., Clements, J., Callaerts, P., D'Hooge, R., & Callaerts-Vegh, Z. (2017). Unpredictable chronic mild stress differentially impairs social and contextual discrimination learning in two inbred mouse strains. PLoS One, 12(11), e0188537. doi:10.1371/journal.pone.0188537
Yamashita, N., Mosinger, B., Roy, A., Miyazaki, M., Ugajin, K., Nakamura, F., . . . Goshima, Y. (2011). CRMP5 (collapsin response mediator protein 5) regulates dendritic development and synaptic plasticity in the cerebellar Purkinje cells. J Neurosci, 31(5), 1773-1779. doi:10.1523/jneurosci.5337-10.2011
Yoshimura, T., Kawano, Y., Arimura, N., Kawabata, S., Kikuchi, A., & Kaibuchi, K. (2005). GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell, 120(1), 137-149. doi:10.1016/j.cell.2004.11.012
Zigova, T., Pencea, V., Wiegand, S. J., & Luskin, M. B. (1998). Intraventricular administration of BDNF increases the number of newly generated neurons in the adult olfactory bulb. Mol Cell Neurosci, 11(4), 234-245. doi:10.1006/mcne.1998.0684