Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Sex Differences in Autism-Like Behavioral Phenotypes and Postsynaptic Receptors Expression in the Prefrontal Cortex of TERT Transgenic Mice

  • Kim, Ki Chan (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Cho, Kyu Suk (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Yang, Sung Min (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Gonzales, Edson Luck (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Valencia, Schley (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Eun, Pyeong Hwa (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Choi, Chang Soon (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Mabunga, Darine Froy (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Kim, Ji-Woon (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Noh, Judy Kyoungju (College of Human Ecology, Cornell University) ;
  • Kim, Hee Jin (Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University) ;
  • Jeon, Se Jin (Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University) ;
  • Han, Seol-Heui (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University) ;
  • Bahn, Geon Ho (Department of Neuropsychiatry, School of Medicine, Kyung Hee University) ;
  • Shin, Chan Young (Center for Neuroscience Research, SMART Institute of Advanced Biomedical Sciences, Konkuk University)
  • Received : 2016.11.01
  • Accepted : 2016.12.06
  • Published : 2017.07.01
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Abstract

Autism spectrum disorder (ASD) remains unexplained and untreated despite the high attention of research in recent years. Aside from its various characteristics is the baffling male preponderance over the female population. Using a validated animal model of ASD which is the telomerase reverse transcriptase overexpressing mice (TERT-tg), we conducted ASD-related behavioral assessments and protein expression experiments to mark the difference between male and females of this animal model. After statistically analyzing the results, we found significant effects of TERT overexpression in sociability, social novelty preference, anxiety, nest building, and electroseizure threshold in the males but not their female littermates. Along these differences are the male-specific increased expressions of postsynaptic proteins which are the NMDA and AMPA receptors in the prefrontal cortex. The vGluT1 presynaptic proteins, but not GAD, were upregulated in both sexes of TERT-tg mice, although it is more significantly pronounced in the male group. Here, we confirmed that the behavioral effect of TERT overexpression in mice was male-specific, suggesting that the aberration of this gene and its downstream pathways preferentially affect the functional development of the male brain, consistent with the male preponderance in ASD.

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References

  1. American Psychiatric Association (2013) The Diagnostic and Statistical Manual of Mental Disorders: DSM 5. bookpoint, USA.
  2. Bakken, T. L., Helverschou, S. B., Eilertsen, D. E., Heggelund, T., Myrbakk, E. and Martinsen, H. (2010) Psychiatric disorders in adolescents and adults with autism and intellectual disability: a representative study in one county in Norway. Res. Dev. Disabil. 31, 1669-1677. https://doi.org/10.1016/j.ridd.2010.04.009
  3. Baron-Cohen, S., Knickmeyer, R. C. and Belmonte, M. K. (2005) Sex differences in the brain: implications for explaining autism. Science 310, 819-823. https://doi.org/10.1126/science.1115455
  4. Baron-Cohen, S. (2009) Autism: the empathizing-systemizing (E-S) theory. Ann. N. Y. Acad. Sci. 1156, 68-80. https://doi.org/10.1111/j.1749-6632.2009.04467.x
  5. Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C. P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S. and Wright, W. E. (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349-352. https://doi.org/10.1126/science.279.5349.349
  6. Bourgeron, T. (2009) A synaptic trek to autism. Curr. Opin. Neurobiol. 19, 231-234. https://doi.org/10.1016/j.conb.2009.06.003
  7. Browning, R. A., Wang, C., Lanker, M. L. and Jobe, P. C. (1990) Electroshock-and pentylenetetrazol-induced seizures in genetically epilepsy-prone rats (GEPRs): differences in threshold and pattern. Epilepsy Res. 6, 1-11. https://doi.org/10.1016/0920-1211(90)90002-D
  8. De Vries, G. and Simerley, R. (2002) Development of Hormone-Dependent Neuronal Systems. In Hormones, Brain and Behaviour. (D. W. Pfaff and M. Joels, Ed.), p. 137. Elsevier.
  9. Deacon, R. (2012) Assessing burrowing, nest construction, and hoarding in mice. J. Vis. Exp. (59), e2607.
  10. Ferron, S. R., Marques-Torrejon, M. A., Mira, H., Flores, I., Taylor, K., Blasco, M. A. and Farinas, I. (2009) Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. J. Neurosci. 29, 14394-14407. https://doi.org/10.1523/JNEUROSCI.3836-09.2009
  11. Giardini, M. A., Segatto, M., da Silva, M. S., Nunes, V. S. and Cano, M. I. (2014) Telomere and telomerase biology. Prog. Mol. Biol. Transl. Sci. 125, 1-40.
  12. Giedd, J. N., Vaituzis, A. C., Hamburger, S. D., Lange, N., Rajapakse, J. C., Kaysen, D., Vauss, Y. C. and Rapoport, J. L. (1996) Quantitative MRI of the temporal lobe, amygdala, and hippocampus in normal human development: ages 4-18 years. J. Comp. Neurol. 366, 223-230. https://doi.org/10.1002/(SICI)1096-9861(19960304)366:2<223::AID-CNE3>3.0.CO;2-7
  13. Halladay, A. K., Bishop, S., Constantino, J. N., Daniels, A. M., Koenig, K., Palmer, K., Messinger, D., Pelphrey, K., Sanders, S. J., Singer, A. T., Taylor, J. L. and Szatmari, P. (2015) Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority. Mol. Autism. 6, 36. https://doi.org/10.1186/s13229-015-0019-y
  14. Harley, C. B., Futcher, A. B. and Greider, C. W. (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345, 458-460. https://doi.org/10.1038/345458a0
  15. Jacquemont, S., Coe, B. P., Hersch, M., Duyzend, M. H., Krumm, N., Bergmann, S., Beckmann, J. S., Rosenfeld, J. A. and Eichler, E. E. (2014) A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. Am. J. Hum. Genet. 94, 415-425. https://doi.org/10.1016/j.ajhg.2014.02.001
  16. Kang, H. J., Choi, Y. S., Hong, S. B., Kim, K. W., Woo, R. S., Won, S. J., Kim, E. J., Jeon, H. K., Jo, S. Y., Kim, T. K., Bachoo, R., Reynolds, I. J., Gwag, B. J. and Lee, H. W. (2004) Ectopic expression of the catalytic subunit of telomerase protects against brain injury resulting from ischemia and NMDA-induced neurotoxicity. J. Neurosci. 24, 1280-1287. https://doi.org/10.1523/JNEUROSCI.4082-03.2004
  17. Kim, J. W., Seung, H., Kwon, K. J., Ko, M. J., Lee, E. J., Oh, H. A., Choi, C. S., Kim, K. C., Gonzales, E. L., You, J. S., Choi, D. H., Lee, J., Han, S. H., Yang, S. M., Cheong, J. H., Shin, C. Y. and Bahn, G. H. (2014a) Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism. PLoS ONE 9, e104927. https://doi.org/10.1371/journal.pone.0104927
  18. Kim, K. C., Choi, C. S., Kim, J. W., Han, S. H., Cheong, J. H., Ryu, J. H. and Shin, C. Y. (2016a) MeCP2 modulates sex differences in the postsynaptic development of the valproate animal model of autism. Mol. Neurobiol. 53, 40-56. https://doi.org/10.1007/s12035-014-8987-z
  19. Kim, K. C., Kim, P., Go, H. S., Choi, C. S., Park, J. H., Kim, H. J., Jeon, S. J., Dela Pena, I. C., Han, S. H., Cheong, J. H., Ryu, J. H. and Shin, C. Y. (2013) Male-specific alteration in excitatory postsynaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder. J. Neurochem. 124, 832-843. https://doi.org/10.1111/jnc.12147
  20. Kim, K. C., Rhee, J., Park, J. E., Lee, D. K., Choi, C. S., Kim, J. W., Lee, H. W., Song, M. R., Yoo, H. J. and Shin, C. Y. (2016b) Overexpression of telomerase reverse transcriptase induces autism-like excitatory phenotypes in mice. Mol. Neurobiol. 53, 7312-7328. https://doi.org/10.1007/s12035-015-9630-3
  21. Kim, N. W., Piatyszek, M. A., Prowse, K. R., Harley, C. B., West, M. D., Ho, P. L., Coviello, G. M., Wright, W. E., Weinrich, S. L. and Shay, J. W. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011-2015. https://doi.org/10.1126/science.7605428
  22. Kim, Y. S., Leventhal, B. L., Koh, Y.-J., Fombonne, E., Laska, E., Lim, E.-C., Cheon, K.-A., Kim, S.-J., Kim, Y.-K., Lee, H., Song, D. H. and Grinker, R. R. (2011) Prevalence of autism spectrum disorders in a total population sample. Am. J. Psychiatry 168, 904-912. https://doi.org/10.1176/appi.ajp.2011.10101532
  23. Klapper, W., Shin, T. and Mattson, M. P. (2001) Differential regulation of telomerase activity and TERT expression during brain development in mice. J. Neurosci. Res. 64, 252-260. https://doi.org/10.1002/jnr.1073
  24. Kurian, J. R., Forbes-Lorman, R. M. and Auger, A. P. (2007) Sex difference in mecp2 expression during a critical period of rat brain development. Epigenetics 2, 173-178. https://doi.org/10.4161/epi.2.3.4841
  25. Larson, T., Anckarsater, H., Gillberg, C., Stahlberg, O., Carlstrom, E., Kadesjo, B., Rastam, M., Lichtenstein, P. and Gillberg, C. (2010) The autism-tics, AD/HD and other comorbidities inventory (ATAC): further validation of a telephone interview for epidemiological research. BMC Psychiatry 10, 1. https://doi.org/10.1186/1471-244X-10-1
  26. Litchfield, J. T., Jr. and Wilcoxon, F. (1949) A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96, 99-113.
  27. Liu, M., Hu, Y., Zhu, L., Chen, C., Zhang, Y., Sun, W. and Zhou, Q. (2012) Overexpression of the mTERT gene by adenoviral vectors promotes the proliferation of neuronal stem cells in vitro and stimulates neurogenesis in the hippocampus of mice. J. Biomed. Res. 26, 381-388. https://doi.org/10.7555/JBR.26.20110078
  28. Luders, E., Narr, K., Thompson, P., Woods, R., Rex, D., Jancke, L., Steinmetz, H. and Toga, A. (2005) Mapping cortical gray matter in the young adult brain: effects of gender. Neuroimage 26, 493-501. https://doi.org/10.1016/j.neuroimage.2005.02.010
  29. Markram, K., Rinaldi, T., La Mendola, D., Sandi, C. and Markram, H. (2008) Abnormal fear conditioning and amygdala processing in an animal model of autism. Neuropsychopharmacology 33, 901-912. https://doi.org/10.1038/sj.npp.1301453
  30. McCarthy, M. M., Auger, A. P., Bale, T. L., De Vries, G. J., Dunn, G. A., Forger, N. G., Murray, E. K., Nugent, B. M., Schwarz, J. M. and Wilson, M. E. (2009) The epigenetics of sex differences in the brain. J. Neurosci. 29, 12815-12823. https://doi.org/10.1523/JNEUROSCI.3331-09.2009
  31. Noldus, L. P., Spink, A. J. and Tegelenbosch, R. A. (2001) EthoVision: a versatile video tracking system for automation of behavioral experiments. Behav. Res. Methods Instrum. Comput. 33, 398-414. https://doi.org/10.3758/BF03195394
  32. Panksepp, J. B. and Lahvis, G. P. (2011) Rodent empathy and affective neuroscience. Neurosci. Biobehav. Rev. 35, 1864-1875. https://doi.org/10.1016/j.neubiorev.2011.05.013
  33. Park, H. G., Yoon, S. Y., Choi, J. Y., Lee, G. S., Choi, J. H., Shin, C. Y., Son, K. H., Lee, Y. S., Kim, W. K., Ryu, J. H., Ko, K. H. and Cheong, J. H. (2007) Anticonvulsant effect of wogonin isolated from Scutellaria baicalensis. Eur. J. Pharmacol. 574, 112-119. https://doi.org/10.1016/j.ejphar.2007.07.011
  34. Pellow, S. and File, S. E. (1986) Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol. Biochem. Behav. 24, 525-529. https://doi.org/10.1016/0091-3057(86)90552-6
  35. Rinaldi, T., Kulangara, K., Antoniello, K. and Markram, H. (2007) Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. Proc. Natl. Acad. Sci. U.S.A. 104, 13501-13506. https://doi.org/10.1073/pnas.0704391104
  36. Robinson, E. B., Lichtenstein, P., Anckarsater, H., Happe, F. and Ronald, A. (2013) Examining and interpreting the female protective effect against autistic behavior. Proc. Natl. Acad. Sci. U.S.A. 110, 5258-5262. https://doi.org/10.1073/pnas.1211070110
  37. Rubenstein, J. and Merzenich, M. (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255-267. https://doi.org/10.1034/j.1601-183X.2003.00037.x
  38. Schneider, T., Roman, A., Basta-Kaim, A., Kubera, M., Budziszewska, B., Schneider, K. and Przewlocki, R. (2008) Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology 33, 728-740. https://doi.org/10.1016/j.psyneuen.2008.02.011
  39. Silverman, J. L., Yang, M., Lord, C. and Crawley, J. N. (2010) Behavioural phenotyping assays for mouse models of autism. Nat. Rev. Neurosci. 11, 490-502. https://doi.org/10.1038/nrn2851
  40. Skuse, D. H. (2000) Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism. Pediatr. Res. 47, 9-16. https://doi.org/10.1203/00006450-200001000-00006
  41. Spijker, S. (2011) Dissection of rodent brain regions. Neuroproteomics 57, 13-26.
  42. Storch, E. A., Wood, J. J., Ehrenreich-May, J., Jones, A. M., Park, J. M., Lewin, A. B. and Murphy, T. K. (2012) Convergent and discriminant validity and reliability of the pediatric anxiety rating scale in youth with autism spectrum disorders. J. Autism Dev. Disord. 42, 2374-2382. https://doi.org/10.1007/s10803-012-1489-9
  43. Tsai, H.-W., Grant, P. A. and Rissman, E. F. (2009) Sex differences in histone modifications in the neonatal mouse brain. Epigenetics 4, 47-53. https://doi.org/10.4161/epi.4.1.7288
  44. Ueno, K. I., Togashi, H., Mori, K., Matsumoto, M., Ohashi, S., Hoshino, A., Fujita, T., Saito, H., Minami, M. and Yoshioka, M. (2002) Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder. Behav. Pharmacol. 13, 1-13. https://doi.org/10.1097/00008877-200202000-00001
  45. Yuan, E., Tsai, P. T., Greene-Colozzi, E., Sahin, M., Kwiatkowski, D. J. and Malinowska, I. A. (2012) Graded loss of tuberin in an allelic series of brain models of TSC correlates with survival, and biochemical, histological and behavioral features. Hum. Mol. Genet. dds262.
  46. Zorumski, C. F. and Izumi, Y. (2012) NMDA receptors and metaplasticity: mechanisms and possible roles in neuropsychiatric disorders. Neurosci. Biobehav. Rev. 36, 989-1000. https://doi.org/10.1016/j.neubiorev.2011.12.011

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