Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Autism-Like Behavioral Phenotypes in Mice Treated with Systemic N-Methyl-D-Aspartate

  • Adil, Keremkleroo Jym (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Gonzales, Edson Luck (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Remonde, Chilly Gay (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Boo, Kyung-Jun (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Jeon, Se Jin (School of Medicine and Center for Neuroscience Research, Konkuk University) ;
  • Shin, Chan Young (School of Medicine and Center for Neuroscience Research, Konkuk University)
  • Received : 2021.08.09
  • Accepted : 2021.09.17
  • Published : 2022.05.01
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Abstract

Autism spectrum disorder (ASD) having core characteristics of social interaction problems and repetitive behaviors and interests affects individuals at varying degrees and comorbidities, making it difficult to determine the precise etiology underlying the symptoms. Given its heterogeneity, ASD is difficult to treat and the development of therapeutics is slow due to the scarcity of animal models that are easy to produce and screen with. Based on the theory of excitation/inhibition imbalance in the brain with ASD which involves glutamatergic and/or GABAergic neurotransmission, a pharmacologic agent to modulate these receptors might be a good starting point for modeling. N-methyl-D-aspartic acid (NMDA) is an amino acid derivative acting as a specific agonist at the NMDA receptor and therefore imitates the action of the neurotransmitter glutamate on that receptor. In contrast to glutamate, NMDA selectively binds to and regulates the NMDA receptor, but not other glutamate receptors such as AMPA and kainite receptors. Given this role, we aimed to determine whether NMDA administration could result in autistic-like behavior in adolescent mice. Both male and female mice were treated with saline or NMDA (50 and 75 mg/kg) and were tested on various behavior experiments. Interestingly, acute NMDA-treated mice showed social deficits and repetitive behavior similar to ASD phenotypes. These results support the excitation/inhibition imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model of ASD-like behaviors.

Keywords

Acknowledgement

This work was supported by the KIST (Grant No. 2E30190-20-060) and the National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2016R1A5A2012284)

References

  1. Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, E. and Rutter, M. (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63-77. https://doi.org/10.1017/S0033291700028099
  2. Baranova, J., Dragunas, G., Botellho, M. C., Ayub, A. L. P., Bueno-Alves, R., Alencar, R. R., Papaiz, D. D., Sogayar, M. C., Ulrich, H. and Correa, R. G. (2021) Autism spectrum disorder: signaling pathways and prospective therapeutic targets. Cell. Mol. Neurobiol. 41, 619-649. https://doi.org/10.1007/s10571-020-00882-7
  3. Bey, A. L., Wang, X., Yan, H., Kim, N., Passman, R. L., Yang, Y., Cao, X., Towers, A. J., Hulbert, S. W., Duffney, L. J., Gaidis, E., Rodriguiz, R. M., Wetsel, W. C., Yin, H. H. and Jiang, Y. h. (2018) Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors. Transl. Psychiatry 8, 94. https://doi.org/10.1038/s41398-018-0142-6
  4. Bristot Silvestrin, R., Bambini-Junior, V., Galland, F., Daniele Bobermim, L., Quincozes-Santos, A., Torres Abib, R., Zanotto, C., Batassini, C., Brolese, G., Goncalves, C. A., Riesgo, R. and Gottfried, C. (2013) Animal model of autism induced by prenatal exposure to valproate: altered glutamate metabolism in the hippocampus. Brain Res. 1495, 52-60. https://doi.org/10.1016/j.brainres.2012.11.048
  5. Burgdorf, J., Moskal, J. R., Brudzynski, S. M. and Panksepp, J. (2013) Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for autism spectrum disorders: a role for NMDA receptors. Behav. Brain Res. 251, 18-24. https://doi.org/10.1016/j.bbr.2013.04.022
  6. Cheroni, C., Caporale, N. and Testa, G. (2020) Autism spectrum disorder at the crossroad between genes and environment: contributions, convergences, and interactions in ASD developmental pathophysiology. Mol. Autism 11, 69. https://doi.org/10.1186/s13229-020-00370-1
  7. Constantino, J. N. and Todd, R. D. (2003) Autistic traits in the general population: a twin study. Arch. Gen. Psychiatry 60, 524-530. https://doi.org/10.1001/archpsyc.60.5.524
  8. Conti, F. (1997) Localization of NMDA receptors in the cerebral cortex: a schematic overview. Braz. J. Med. Biol. Res. 30, 555-560. https://doi.org/10.1590/S0100-879X1997000500001
  9. Donner, N. C. and Lowry, C. A. (2013) Sex differences in anxiety and emotional behavior. Pflugers Arch. 465, 601-626. https://doi.org/10.1007/s00424-013-1271-7
  10. El-Kordi, A., Winkler, D., Hammerschmidt, K., Kastner, A., Krueger, D., Ronnenberg, A., Ritter, C., Jatho, J., Radyushkin, K., Bourgeron, T., Fischer, J., Brose, N. and Ehrenreich, H. (2013) Development of an autism severity score for mice using Nlgn4 null mutants as a construct-valid model of heritable monogenic autism. Behav. Brain Res. 251, 41-49. https://doi.org/10.1016/j.bbr.2012.11.016
  11. Frye, C. A. and Llaneza, D. C. (2010) Corticosteroid and neurosteroid dysregulation in an animal model of autism, BTBR mice. Physiol. Behav. 100, 264-267. https://doi.org/10.1016/j.physbeh.2010.03.005
  12. Gandhi, T. and Lee, C. C. (2021) Neural mechanisms underlying repetitive behaviors in rodent models of autism spectrum disorders. Front. Cell. Neurosci. 14, 592710. https://doi.org/10.3389/fncel.2020.592710
  13. Goebel, D. J. and Poosch, M. S. (1999) NMDA receptor subunit gene expression in the rat brain: a quantitative analysis of endogenous mRNA levels of NR1Com, NR2A, NR2B, NR2C, NR2D and NR3A. Mol. Brain Res. 69, 164-170. https://doi.org/10.1016/S0169-328X(99)00100-X
  14. Goncalves, J., Violante, I. R., Sereno, J., Leitao, R. A., Cai, Y., Abrunhosa, A., Silva, A. P., Silva, A. J. and Castelo-Branco, M. (2017) Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes. Mol. Autism 8, 47. https://doi.org/10.1186/s13229-017-0166-4
  15. Hines, R. M., Wu, L., Hines, D. J., Steenland, H., Mansour, S., Dahlhaus, R., Singaraja, R. R., Cao, X., Sammler, E., Hormuzdi, S. G., Zhuo, M. and El-Husseini, A. (2008) Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression. J. Neurosci. 28, 6055-6067. https://doi.org/10.1523/JNEUROSCI.0032-08.2008
  16. Horder, J., Petrinovic, M. M., Mendez, M. A., Bruns, A., Takumi, T., Spooren, W., Barker, G. J., Kunnecke, B. and Murphy, D. G. (2018) Glutamate and GABA in autism spectrum disorder-a translational magnetic resonance spectroscopy study in man and rodent models. Transl. Psychiatry 8, 106. https://doi.org/10.1038/s41398-018-0155-1
  17. Hughes, H. K., Mills Ko, E., Rose, D. and Ashwood, P. (2018) Immune dysfunction and autoimmunity as pathological mechanisms in autism spectrum disorders. Front. Cell. Neurosci. 12, 405. https://doi.org/10.3389/fncel.2018.00405
  18. Iossifov, I., O'Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., Smith, J. D., Paeper, B., Nickerson, D. A., Dea, J., Dong, S., Gonzalez, L. E., Mandell, J. D., Mane, S. M., Murtha, M. T., Sullivan, C. A., Walker, M. F., Waqar, Z., Wei, L., Willsey, A. J., Yamrom, B., Lee, Y. H., Grabowska, E., Dalkic, E., Wang, Z., Marks, S., Andrews, P., Leotta, A., Kendall, J., Hakker, I., Rosenbaum, J., Ma, B., Rodgers, L., Troge, J., Narzisi, G., Yoon, S., Schatz, M. C., Ye, K., McCombie, W. R., Shendure, J., Eichler, E. E., State, M. W. and Wigler, M. (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216-221. https://doi.org/10.1038/nature13908
  19. Jeon, S. J., Gonzales, E. L., Mabunga, D. F. N., Valencia, S. T., Kim, D. G., Kim, Y., Adil, K. J. L., Shin, D., Park, D. and Shin, C. Y. (2018) Sex-specific behavioral features of rodent models of autism spectrum disorder. Exp. Neurobiol. 27, 321-343. https://doi.org/10.5607/en.2018.27.5.321
  20. Kalueff, A. V., Stewart, A. M., Song, C., Berridge, K. C., Graybiel, A. M. and Fentress, J. C. (2016) Neurobiology of rodent self-grooming and its value for translational neuroscience. Nat. Rev. Neurosci. 17, 45-59. https://doi.org/10.1038/nrn.2015.8
  21. Kim, D. G., Gonzales, E. L., Kim, S., Kim, Y., Adil, K. J., Jeon, S. J., Cho, K. S., Kwon, K. J. and Shin, C. Y. (2019) Social interaction test in home cage as a novel and ethological measure of social behavior in mice. Exp. Neurobiol. 28, 247. https://doi.org/10.5607/en.2019.28.2.247
  22. Kim, J. W., Park, K., Kang, R. J., Gonzales, E. L. T., Kim, D. G., Oh, H. A., Seung, H., Ko, M. J., Kwon, K. J., Kim, K. C., Lee, S. H., Chung, C. and Shin, C. Y. (2018) Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism. Neuropsychopharmacology 44, 314-323. https://doi.org/10.1038/s41386-018-0098-5
  23. Kim, K. C., Gonzales, E. L., Lazaro, M. T., Choi, C. S., Bahn, G. H., Yoo, H. J. and Shin, C. Y. (2016) Clinical and neurobiological relevance of current animal models of autism spectrum disorders. Biomol. Ther. (Seoul) 24, 207-243. https://doi.org/10.4062/biomolther.2016.061
  24. Law, A. J., Weickert, C. S., Webster, M. J., Herman, M. M., Kleinman, J. E. and Harrison, P. J. (2003) Expression of NMDA receptor NR1, NR2A and NR2B subunit mRNAs during development of the human hippocampal formation. Eur. J. Neurosci. 18, 1197-1205. https://doi.org/10.1046/j.1460-9568.2003.02850.x
  25. Lazaro, M. T., Taxidis, J., Shuman, T., Bachmutsky, I., Ikrar, T., Santos, R., Marcello, G. M., Mylavarapu, A., Chandra, S., Foreman, A., Goli, R., Tran, D., Sharma, N., Azhdam, M., Dong, H., Choe, K. Y., Penagarikano, O., Masmanidis, S. C., Racz, B., Xu, X., Geschwind, D. H. and Golshani, P. (2019) Reduced prefrontal synaptic connectivity and disturbed oscillatory population dynamics in the CNTNAP2 model of autism. Cell Rep. 27, 2567-2578.e6. https://doi.org/10.1016/j.celrep.2019.05.006
  26. Lee, E., Lee, J. and Kim, E. (2017) Excitation/inhibition imbalance in animal models of autism spectrum disorders. Biol. Psychiatry 81, 838-847. https://doi.org/10.1016/j.biopsych.2016.05.011
  27. Lopatina, O. L., Komleva, Y. K., Gorina, Y. V., Olovyannikova, R. Y., Trufanova, L. V., Hashimoto, T., Takahashi, T., Kikuchi, M., Minabe, Y., Higashida, H. and Salmina, A. B. (2018) Oxytocin and excitation/inhibition balance in social recognition. Neuropeptides 72, 1-11. https://doi.org/10.1016/j.npep.2018.09.003
  28. Masi, A., DeMayo, M. M., Glozier, N. and Guastella, A. J. (2017) An overview of autism spectrum disorder, heterogeneity and treatment options. Neurosci. Bull. 33, 183-193. https://doi.org/10.1007/s12264-017-0100-y
  29. Mohammadi, S., Asadi-Shekaari, M., Basiri, M., Parvan, M., Shabani, M. and Nozari, M. (2020) Improvement of autistic-like behaviors in adult rats prenatally exposed to valproic acid through early suppression of NMDA receptor function. Psychopharmacology 237, 199-208. https://doi.org/10.1007/s00213-019-05357-2
  30. Morgan, D., Munireddy, S., Alamed, J., DeLeon, J., Diamond, D. M., Bickford, P., Hutton, M., Lewis, J., McGowan, E. and Gordon, M. N. (2008) Apparent behavioral benefits of tau overexpression in P301L tau transgenic mice. J. Alzheimers Dis. 15, 605-614. https://doi.org/10.3233/JAD-2008-15407
  31. Patterson, P. H. (2011) Modeling autistic features in animals. Pediatr. Res. 69, 34R-40R. https://doi.org/10.1203/PDR.0b013e318212b80f
  32. Pitkanen, A., Schwartzkroin, P. A. and Moshe, S. L. (2005) Models of Seizures and Epilepsy. Academic Press.
  33. Rubenstein, J. L. and Merzenich, M. 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
  34. Saitow, F., Takumi, T. and Suzuki, H. (2020) Change in serotonergic modulation contributes to the synaptic imbalance of neuronal circuit at the prefrontal cortex in the 15q11-13 duplication mouse model of autism. Neuropharmacology 165, 107931. https://doi.org/10.1016/j.neuropharm.2019.107931
  35. Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., Walker, M. F., Ober, G. T., Teran, N. A., Song, Y., El-Fishawy, P., Murtha, R. C., Choi, M., Overton, J. D., Bjornson, R. D., Carriero, N. J., Meyer, K. A., Bilguvar, K., Mane, S. M., Sestan, N., Lifton, R. P., Gunel, M., Roeder, K., Geschwind, D. H., Devlin, B. and State, M. W. (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237-241. https://doi.org/10.1038/nature10945
  36. Schroeder, J. C., Reim, D., Boeckers, T. M. and Schmeisser, M. J. (2015) Genetic animal models for autism spectrum disorder. In Social Behavior from Rodents to Humans, pp. 311-324. Springer.
  37. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y. H., Hicks, J., Spence, S. J., Lee, A. T., Puura, K., Lehtimaki, T., Ledbetter, D., Gregersen, P. K., Bregman, J., Sutcliffe, J. S., Jobanputra, V., Chung, W., Warburton, D., King, M. C., Skuse, D., Geschwind, D. H., Gilliam, T. C., Ye, K. and Wigler, M. (2007) Strong association of de novo copy number mutations with autism. Science 316, 445-449. https://doi.org/10.1126/science.1138659
  38. Smalley, S. L. (1997) Genetic influences in childhood-onset psychiatric disorders: autism and attention-deficit/hyperactivity disorder. Am. J. Hum. Genet. 60, 1276-1282. https://doi.org/10.1086/515485
  39. Stafstrom, C. E. and Sasaki-Adams, D. M. (2003) NMDA-induced seizures in developing rats cause long-term learning impairment and increased seizure susceptibility. Epilepsy Res. 53, 129-137. https://doi.org/10.1016/S0920-1211(02)00258-9
  40. Uzunova, G., Pallanti, S. and Hollander, E. (2016) Excitatory/inhibitory imbalance in autism spectrum disorders: implications for interventions and therapeutics. World J. Biol. Psychiatry 17, 174-186. https://doi.org/10.3109/15622975.2015.1085597
  41. Werling, D. M. and Geschwind, D. H. (2013) Sex differences in autism spectrum disorders. Curr. Opin. Neurol. 26, 146-153. https://doi.org/10.1097/WCO.0b013e32835ee548
  42. Zerbi, V., Markicevic, M., Gasparini, F., Schroeter, A., Rudin, M. and Wenderoth, N. (2019) Inhibiting mGluR5 activity by AFQ056/Mavoglurant rescues circuit-specific functional connectivity in Fmr1 knockout mice. Neuroimage 191, 392-402. https://doi.org/10.1016/j.neuroimage.2019.02.051