Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Behavioral Deficits in Adolescent Mice after Sub-Chronic Administration of NMDA during Early Stage of Postnatal Development

  • Adil, Keremkleroo Jym (Department of Pharmacology, School of Medicine, Konkuk University) ;
  • Remonde, Chilly Gay (Department of Pharmacology, School of Medicine, Konkuk University) ;
  • Gonzales, Edson Luck (Department of Pharmacology, School of Medicine, Konkuk University) ;
  • Boo, Kyung-Jun (Department of Pharmacology, School of Medicine, Konkuk University) ;
  • Kwon, Kyong Ja (Department of Pharmacology, School of Medicine, Konkuk University) ;
  • Kim, Dong Hyun (Department of Pharmacology, School of Medicine, Konkuk University) ;
  • Kim, Hee Jin (Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University) ;
  • Cheong, Jae Hoon (School of Pharmacy, Jeonbuk National University) ;
  • Shin, Chan Young (Department of Pharmacology, School of Medicine, Konkuk University) ;
  • Jeon, Se Jin (Department of Pharmacology, School of Medicine, Konkuk University)
  • Received : 2021.12.26
  • Accepted : 2022.01.11
  • Published : 2022.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Neurodevelopmental disorders are complex conditions that pose difficulty in the modulation of proper motor, sensory and cognitive function due to dysregulated neuronal development. Previous studies have reported that an imbalance in the excitation/inhibition (E/I) in the brain regulated by glutamatergic and/or GABAergic neurotransmission can cause neurodevelopmental and neuropsychiatric behavioral deficits such as autism spectrum disorder (ASD). NMDA acts as an agonist at the NMDA receptor and imitates the action of the glutamate on that receptor. NMDA however, unlike glutamate, only binds to and regulates the NMDA receptor subtypes and not the other glutamate receptors. This study seeks to determine whether NMDA administration in mice i.e., over-activation of the NMDA system would result in long-lasting behavioral deficits in the adolescent mice. Both gender mice were treated with NMDA or saline at early postnatal developmental period with significant synaptogenesis and synaptic maturation. On postnatal day 28, various behavioral experiments were conducted to assess and identify behavioral characteristics. NMDA-treated mice show social deficits, and repetitive behavior in both gender mice at adolescent periods. However, only the male mice but not female mice showed increased locomotor activity. This study implies that neonatal exposure to NMDA may illicit behavioral features similar to ASD. This study also confirms the validity of the E/I imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model for ASD. Future studies may explore the mechanism behind the gender difference in locomotor activity as well as the human relevance and therapeutic significance of the present findings.

Keywords

Acknowledgement

This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean Government (MSIT) (NRF-2017M3A9G2077568) and the NRF (2016R1A5A2012284).

References

  1. Adil, K. J., Gonzales, E. L., Remonde, C. G., Boo, K. J., Jeon, S. J. and Shin, C. Y. (2021) Autism-like behavioral phenotypes in mice treated with systemic N-methyl-D-aspartate. Biomol. Ther. (Seoul) doi: 10.4062/biomolther.2021.133 [Online ahead of print].
  2. American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders: DSM-5. Arlington, VA.
  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. Bejjani, A., O'Neill, J., Kim, J. A., Frew, A. J., Yee, V. W., Ly, R., Kitchen, C., Salamon, N., McCracken, J. T., Toga, A. W., Alger, J. R. and Levitt, J. G. (2012) Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI. PLoS ONE 7, e38786. https://doi.org/10.1371/journal.pone.0038786
  6. Blatt, G. J., Fitzgerald, C. M., Guptill, J. T., Booker, A. B., Kemper, T. L. and Bauman, M. L. (2001) Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J. Autism Dev. Disord. 31, 537-543. https://doi.org/10.1023/A:1013238809666
  7. Blundell, J., Blaiss, C. A., Etherton, M. R., Espinosa, F., Tabuchi, K., Walz, C., Bolliger, M. F., Sudhof, T. C. and Powell, C. M. (2010) Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior. J. Neurosci. 30, 2115-2129. https://doi.org/10.1523/JNEUROSCI.4517-09.2010
  8. Bozzi, Y., Provenzano, G. and Casarosa, S. (2018) Neurobiological bases of autism-epilepsy comorbidity: a focus on excitation/inhibition imbalance. Eur. J. Neurosci. 47, 534-548. https://doi.org/10.1111/ejn.13595
  9. Brann, D. W., Dhandapani, K., Wakade, C., Mahesh, V. B. and Khan, M. M. (2007) Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. Steroids 72, 381-405. https://doi.org/10.1016/j.steroids.2007.02.003
  10. Budreck, E. C., Kwon, O. B., Jung, J. H., Baudouin, S., Thommen, A., Kim, H. S., Fukazawa, Y., Harada, H., Tabuchi, K., Shigemoto, R., Scheiffele, P. and Kim, J. H. (2013) Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling. Proc. Natl. Acad. Sci. U.S.A. 110, 725-730. https://doi.org/10.1073/pnas.1214718110
  11. Castillo-Gomez, E., Perez-Rando, M., Belles, M., Gilabert-Juan, J., Llorens, J. V., Carceller, H., Bueno-Fernandez, C., Garcia-Mompo, C., Ripoll-Martinez, B., Curto, Y., Sebastia-Ortega, N., Molto, M. D., Sanjuan, J. and Nacher, J. (2017) Early social isolation stress and perinatal NMDA receptor antagonist treatment induce changes in the structure and neurochemistry of inhibitory neurons of the adult amygdala and prefrontal cortex. eNeuro 4, ENEURO.0034-17.2017.
  12. Chung, W., Choi, S. Y., Lee, E., Park, H., Kang, J., Park, H., Choi, Y., Lee, D., Park, S. G., Kim, R., Cho, Y. S., Choi, J., Kim, M. H., Lee, J. W., Lee, S., Rhim, I., Jung, M. W., Kim, D., Bae, Y. C. and Kim, E. (2015) Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression. Nat. Neurosci. 18, 435-443. https://doi.org/10.1038/nn.3927
  13. Clancy, B., Finlay, B. L., Darlington, R. B. and Anand, K. J. (2007) Extrapolating brain development from experimental species to humans. Neurotoxicology 28, 931-937. https://doi.org/10.1016/j.neuro.2007.01.014
  14. Coppola, A. and Moshe, S. L. (2012) Animal models. Hand. Clin. Neurol. 107, 63-98. https://doi.org/10.1016/B978-0-444-52898-8.00004-5
  15. Cox, K. H. and Rissman, E. F. (2011) Sex differences in juvenile mouse social behavior are influenced by sex chromosomes and social context. Genes Brain Behav. 10, 465-472. https://doi.org/10.1111/j.1601-183X.2011.00688.x
  16. Du Bois, T. M. and Huang, X. F. (2007) Early brain development disruption from NMDA receptor hypofunction: relevance to schizophrenia. Brain Res. Rev. 53, 260-270. https://doi.org/10.1016/j.brainresrev.2006.09.001
  17. Edwards, K. A. and Zup, S. L. (2021) Serotonin pretreatment abolishes sex-specific NMDA-induced seizure behavior in developing rats. Neuroscience 463, 184-196. https://doi.org/10.1016/j.neuroscience.2021.03.033
  18. Ey, E., Leblond, C. S. and Bourgeron, T. (2011) Behavioral profiles of mouse models for autism spectrum disorders. Autism Res. 4, 5-16. https://doi.org/10.1002/aur.175
  19. Foss-Feig, J. H., Adkinson, B. D., Ji, J. L., Yang, G., Srihari, V. H., McPartland, J. C., Krystal, J. H., Murray, J. D. and Anticevic, A. (2017) Searching for cross-diagnostic convergence: neural mechanisms governing excitation and inhibition balance in schizophrenia and autism spectrum disorders. Biol. Psychiatry 81, 848-861. https://doi.org/10.1016/j.biopsych.2017.03.005
  20. Fukuchi, M., Nii, T., Ishimaru, N., Minamino, A., Hara, D., Takasaki, I., Tabuchi, A. and Tsuda, M. (2009) Valproic acid induces up- or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions. Neurosci. Res. 65, 35-43. https://doi.org/10.1016/j.neures.2009.05.002
  21. Golitabari, N., Mohammadian, F., Salari, A. A. and Amani, M. (2021) Neonatal NMDA blockade alters the LTP, LTD and cognitive functions in male and female Wistar rats. Neuropharmacology 205, 108896.
  22. 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
  23. Haida, O., Al Sagheer, T., Balbous, A., Francheteau, M., Matas, E., Soria, F., Fernagut, P. O. and Jaber, M. (2019) Sex-dependent behavioral deficits and neuropathology in a maternal immune activation model of autism. Transl. Psychiatry 9, 124. https://doi.org/10.1038/s41398-019-0457-y
  24. Horvath, K. M., Hartig, W., Van der Veen, R., Keijser, J. N., Mulder, J., Ziegert, M., Van der Zee, E. A., Harkany, T. and Luiten, P. G. (2002) 17β-Estradiol enhances cortical cholinergic innervation and preserves synaptic density following excitotoxic lesions to the rat nucleus basalis magnocellularis. Neuroscience 110, 489-504. https://doi.org/10.1016/S0306-4522(01)00560-7
  25. 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
  26. Jang, J. H., Nam, T. S., Jun, J., Jung, S. J., Kim, D. W. and Leem, J. W. (2015) Peripheral NMDA receptors mediate antidromic nerve stimulation-induced tactile hypersensitivity in the rat. Mediators Inflamm. 2015, 793624. https://doi.org/10.1155/2015/793624
  27. Jeste, S. S. and Tuchman, R. (2015) Autism spectrum disorder and epilepsy: two sides of the same coin? J. Child Neurol. 30, 1963-1971. https://doi.org/10.1177/0883073815601501
  28. Kabova, R., Liptakova, S., Slamberova, R., Pometlova, M. and Velisek, L. (1999) Age-specific N-methyl-D-aspartate-induced seizures: perspectives for the west syndrome model. Epilepsia 40, 1357-1369. https://doi.org/10.1111/j.1528-1157.1999.tb02006.x
  29. Kalkbrenner, K. A. and Standley, C. A. (2003) Estrogen modulation of NMDA-induced seizures in ovariectomized and non-ovariectomized rats. Brain Res. 964, 244-249. https://doi.org/10.1016/S0006-8993(02)04065-9
  30. 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
  31. Kang, J. and Kim, E. (2015) Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improves social deficits and repetitive behaviors. Front. Mol. Neurosci. 8, 17. https://doi.org/10.3389/fnmol.2015.00017
  32. Kim, J. A., Szatmari, P., Bryson, S. E., Streiner, D. L. and Wilson, F. J. (2000) The prevalence of anxiety and mood problems among children with autism and Asperger syndrome. Autism 4, 117-132. https://doi.org/10.1177/1362361300004002002
  33. 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. (2019a) 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
  34. Kim, J. W., Seung, H., Kim, K. C., Gonzales, E. L. T., Oh, H. A., Yang, S. M., Ko, M. J., Han, S. H., Banerjee, S. and Shin, C. Y. (2017) Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism. Neuropharmacology 113, 71-81. https://doi.org/10.1016/j.neuropharm.2016.09.014
  35. 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
  36. Kim, K. C., Choi, C. S., Kim, J. W., Han, S. H., Cheong, J. H., Ryu, J. H. and Shin, C. Y. (2016) 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
  37. Kim, K. C., Kim, P., Go, H. S., Choi, C. S., Yang, S. I., Cheong, J. H., Shin, C. Y. and Ko, K. H. (2011) The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol. Lett. 201, 137-142. https://doi.org/10.1016/j.toxlet.2010.12.018
  38. Kim, K. C., Lee, D. K., Go, H. S., Kim, P., Choi, C. S., Kim, J. W., Jeon, S. J., Song, M. R. and Shin, C. Y. (2014b) Pax6-dependent cortical glutamatergic neuronal differentiation regulates autism-like behavior in prenatally valproic acid-exposed rat offspring. Mol. Neurobiol. 49, 512-528. https://doi.org/10.1007/s12035-013-8535-2
  39. Kim, S., Kim, D. G., Gonzales, E. L., Mabunga, D. F. N., Shin, D., Jeon, S. J., Shin, C. Y., Ahn, T. and Kwon, K. J. (2019b) Effects of intraperitoneal N-methyl-D-aspartate (NMDA) administration on nociceptive/repetitive behaviors in juvenile mice. Biomol. Ther. (Seoul) 27, 168-177. https://doi.org/10.4062/biomolther.2018.230
  40. Kim, Y. S. and Leventhal, B. L. (2015) Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders. Biol. Psychiatry 77, 66-74. https://doi.org/10.1016/j.biopsych.2014.11.001
  41. Kishikawa, Y., Kawahara, Y., Yamada, M., Kaneko, F., Kawahara, H. and Nishi, A. (2014) The spontaneously hypertensive rat/Izm (SHR/Izm) shows attention deficit/hyperactivity disorder-like behaviors but without impulsive behavior: therapeutic implications of low-dose methylphenidate. Behav. Brain Res. 274, 235-242. https://doi.org/10.1016/j.bbr.2014.08.026
  42. LaSalle, J. M. (2013) Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J. Hum. Genet. 58, 396-401. https://doi.org/10.1038/jhg.2013.49
  43. Latusz, J. and Mackowiak, M. (2020) Early-life blockade of NMDA receptors induces epigenetic abnormalities in the adult medial prefrontal cortex: possible involvement in memory impairment in trace fear conditioning. Psychopharmacology 237, 231-248. https://doi.org/10.1007/s00213-019-05362-5
  44. Leblond, C. S., Nava, C., Polge, A., Gauthier, J., Huguet, G., Lumbroso, S., Giuliano, F., Stordeur, C., Depienne, C., Mouzat, K., Pinto, D., Howe, J., Lemiere, N., Durand, C. M., Guibert, J., Ey, E., Toro, R., Peyre, H., Mathieu, A., Amsellem, F., Rastam, M., Gillberg, I. C., Rappold, G. A., Holt, R., Monaco, A. P., Maestrini, E., Galan, P., Heron, D., Jacquette, A., Afenjar, A., Rastetter, A., Brice, A., Devillard, F., Assouline, B., Laffargue, F., Lespinasse, J., Chiesa, J., Rivier, F., Bonneau, D., Regnault, B., Zelenika, D., Delepine, M., Lathrop, M., Sanlaville, D., Schluth-Bolard, C., Edery, P., Perrin, L., Tabet, A. C., Schmeisser, M. J., Boeckers, T. M., Coleman, M., Sato, D., Szatmari, P., Scherer, S. W., Rouleau, G. A., Betancur, C., Leboyer, M., Gillberg, C., Delorme, R. and Bourgeron, T. (2014) Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 10, e1004580. https://doi.org/10.1371/journal.pgen.1004580
  45. Lemmens, E. M., Lubbers, T., Schijns, O. E., Beuls, E. A. and Hoogland, G. (2005) Gender differences in febrile seizure-induced proliferation and survival in the rat dentate gyrus. Epilepsia 46, 1603-1612. https://doi.org/10.1111/j.1528-1167.2005.00252.x
  46. Leyfer, O. T., Folstein, S. E., Bacalman, S., Davis, N. O., Dinh, E., Morgan, J., Tager-Flusberg, H. and Lainhart, J. E. (2006) Comorbid psychiatric disorders in children with autism: Interview development and rates of disorders. J. Autism Dev. Disord. 36, 849-861. https://doi.org/10.1007/s10803-006-0123-0
  47. Liu, S. b. and Zhao, M. g. (2013) Neuroprotective effect of estrogen: role of nonsynaptic NR2B-containing NMDA receptors. Brain Res. Bull. 93, 27-31. https://doi.org/10.1016/j.brainresbull.2012.10.004
  48. Maenner, M. J., Shaw, K. A., Baio, J., Washington, A., Patrick, M., DiRienzo, M., Christensen, D. L., Wiggins, L. D., Pettygrove, S., Andrews, J. G., Lopez, M., Hudson, A., Baroud, T., Schwenk, Y., White, T., Rosenberg, C. R., Lee, L. C., Harrington, R. A., Huston, M., Hewitt, A., Esler, A., Hall-Lande, J., Poynter, J. N., Hallas-Muchow, L., Constantino, J. N., Fitzgerald, R. T., Zahorodny, W., Shenouda, J., Daniels, J. L., Warren, Z., Vehorn, A., Salinas, A., Durkin, M. S. and Dietz, P. M. (2020) Prevalence of autism spectrum disorder among children aged 8 years-autism and developmental disabilities monitoring network, 11 sites, United States, 2016. MMWR Surveill. Summ. 69, 1-12.
  49. McCarthy, M. M., Davis, A. M. and Mong, J. A. (1997) Excitatory neurotransmission and sexual differentiation of the brain. Brain Res. Bull. 44, 487-495. https://doi.org/10.1016/S0361-9230(97)00230-X
  50. Meidenbauer, J. J., Mantis, J. G. and Seyfried, T. N. (2011) The EL mouse: a natural model of autism and epilepsy. Epilepsia 52, 347-357. https://doi.org/10.1111/j.1528-1167.2010.02898.x
  51. Moy, S., Nadler, J., Perez, A., Barbaro, R., Johns, J., Magnuson, T., Piven, J. and Crawley, J. (2004) Sociability and preference for social novelty in five inbred strains: an approach to assess autisticlike behavior in mice. Genes Brain Behav. 3, 287-302. https://doi.org/10.1111/j.1601-1848.2004.00076.x
  52. Oblak, A. L., Gibbs, T. T. and Blatt, G. J. (2011) Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. Brain Res. 1380, 218-228. https://doi.org/10.1016/j.brainres.2010.09.021
  53. Ozsivadjian, A. and Knott, F. (2011) Anxiety problems in young people with autism spectrum disorder: a case series. Clin. Child Psychol. Psychiatry 16, 203-214. https://doi.org/10.1177/1359104511404749
  54. 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
  55. Rinaldi, T., Perrodin, C. and Markram, H. (2008) Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism. Front. Neural Circuits 2, 4. https://doi.org/10.3389/neuro.04.004.2008
  56. Robertson, C. E., Ratai, E. M. and Kanwisher, N. (2016) Reduced GA-BAergic action in the autistic brain. Curr. Biol. 26, 80-85. https://doi.org/10.1016/j.cub.2015.11.019
  57. Rodriguez-Munoz, M., Onetti, Y., Cortes-Montero, E., Garzon, J. and Sanchez-Blazquez, P. (2018) Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor. Mol. Brain 11, 51. https://doi.org/10.1186/s13041-018-0395-2
  58. Roof, R. L. and Hall, E. D. (2000) Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. J. Neurotrauma 17, 367-388. https://doi.org/10.1089/neu.2000.17.367
  59. Rosenberg, R. E., Law, J. K., Yenokyan, G., McGready, J., Kaufmann, W. E. and Law, P. A. (2009) Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch. Pediatr. Adolesc. Med. 163, 907-914. https://doi.org/10.1001/archpediatrics.2009.98
  60. Rubenstein, J. 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
  61. Schneider, T. and Przewlocki, R. (2005) Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 30, 80-89. https://doi.org/10.1038/sj.npp.1300518
  62. Sealey, L., Hughes, B., Sriskanda, A., Guest, J., Gibson, A., JohnsonWilliams, L., Pace, D. and Bagasra, O. (2016) Environmental factors in the development of autism spectrum disorders. Environ. Int. 88, 288-298. https://doi.org/10.1016/j.envint.2015.12.021
  63. Shao, L. R., Habela, C. W. and Stafstrom, C. E. (2019) Pediatric epilepsy mechanisms: expanding the paradigm of excitation/inhibition imbalance. Children 6, 23. https://doi.org/10.3390/children6020023
  64. Shinohe, A., Hashimoto, K., Nakamura, K., Tsujii, M., Iwata, Y., Tsuchiya, K. J., Sekine, Y., Suda, S., Suzuki, K., Sugihara, G., Matsuzaki, H., Minabe, Y., Sugiyama, T., Kawai, M., Iyo, M., Takei, N. and Mori, N. (2006) Increased serum levels of glutamate in adult patients with autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 1472-1477.
  65. 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
  66. Varshney, M. K., Yu, N. Y. L., Katayama, S., Li, X., Liu, T., Wu, W. F., Tohonen, V., Krjutskov, K., Kere, J., Fan, X., Inzunza, J., Gustafsson, J. A. and Nalvarte, I. (2021) Motor function deficits in the estrogen receptor beta knockout mouse: role on excitatory neurotransmission and myelination in the motor cortex. Neuroendocrinology 111, 27-44. https://doi.org/10.1159/000506162
  67. Wang, X., McCoy, P. A., Rodriguiz, R. M., Pan, Y., Je, H. S., Roberts, A. C., Kim, C. J., Berrios, J., Colvin, J. S., Bousquet-Moore, D., Lorenzo, I., Wu, G., Weinberg, R. J., Ehlers, M. D., Philpot, B. D., Beaudet, A. L., Wetsel, W. C. and Jiang, Y. H. (2011) Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3. Hum. Mol. Genet. 20, 3093-3108. https://doi.org/10.1093/hmg/ddr212
  68. Wang, Y. J., Zhang, Y., Liang, X. H., Yang, G. and Zou, L. P. (2012) Effects of adrenal dysfunction and high-dose adrenocorticotropic hormone on NMDA-induced spasm seizures in young Wistar rats. Epilepsy Res. 100, 125-131. https://doi.org/10.1016/j.eplepsyres.2012.02.001
  69. Won, H., Lee, H. R., Gee, H. Y., Mah, W., Kim, J. I., Lee, J., Ha, S., Chung, C., Jung, E. S., Cho, Y. S., Park, S. G., Lee, J. S., Lee, K., Kim, D., Bae, Y. C., Kaang, B. K., Lee, M. G. and Kim, E. (2012) Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261-265. https://doi.org/10.1038/nature11208
  70. Xia, Y., Xing, J. and Krukoff, T. (2009) Neuroprotective effects of R,R-tetrahydrochrysene against glutamate-induced cell death through anti-excitotoxic and antioxidant actions involving estrogen receptor-dependent and -independent pathways. Neuroscience 162, 292-306. https://doi.org/10.1016/j.neuroscience.2009.04.068
  71. Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., O'Shea, D. J., Sohal, V. S., Goshen, I., Finkelstein, J., Paz, J. T., Stehfest, K., Fudim, R., Ramakrishnan, C., Huguenard, J. R., Hegemann, P. and Deisseroth, K. (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171-178. https://doi.org/10.1038/nature10360
  72. Yum, M. S., Lee, M., Woo, D. C., Kim, D. W., Ko, T. S. and Velisek, L. (2015) β-Hydroxybutyrate attenuates NMDA-induced spasms in rats with evidence of neuronal stabilization on MR spectroscopy. Epilepsy Res. 117, 125-132. https://doi.org/10.1016/j.eplepsyres.2015.08.005
  73. Zerbo, O., Qian, Y., Yoshida, C., Grether, J. K., Van de Water, J. and Croen, L. A. (2015) Maternal infection during pregnancy and autism spectrum disorders. J. Autism Dev. Disord. 45, 4015-4025. https://doi.org/10.1007/s10803-013-2016-3