Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2 −/− Mice

Changuk Chung, Seungmin Ha, Hyojin Kang, Jiseok Lee, Seung Min Um, Haidun Yan, Ye Eun Yoo, Taesun Yoo, Hwajin Jung, Dongwon Lee, Eunee Lee, Seungjoon Lee, Jihye Kim, Ryunhee Kim, Yonghan Kwon, Woohyun Kim, Hyosang Kim, Lara Duffney, Doyoun Kim, Won MahHyejung Won, Seojung Mo, Jin Yong Kim, Chae Seok Lim, Bong Kiun Kaang, Tobias M. Boeckers, Yeonseung Chung, Hyun Kim, Yong hui Jiang, Eunjoon Kim

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder–related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. Methods: We used Shank2 −/− mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. Results: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2 −/− mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype—NMDAR hyperfunction—at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7–P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). Conclusions: Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2 −/− mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.

Original languageEnglish
Pages (from-to)534-543
Number of pages10
JournalBiological Psychiatry
Volume85
Issue number7
DOIs
Publication statusPublished - 2019 Apr 1

Keywords

  • Autism
  • Memantine
  • NMDA receptor
  • SHANK2
  • Synapse
  • Treatment

ASJC Scopus subject areas

  • Biological Psychiatry

Fingerprint Dive into the research topics of 'Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2 <sup>−/−</sup> Mice'. Together they form a unique fingerprint.

  • Cite this

    Chung, C., Ha, S., Kang, H., Lee, J., Um, S. M., Yan, H., Yoo, Y. E., Yoo, T., Jung, H., Lee, D., Lee, E., Lee, S., Kim, J., Kim, R., Kwon, Y., Kim, W., Kim, H., Duffney, L., Kim, D., ... Kim, E. (2019). Early Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2 −/− Mice Biological Psychiatry, 85(7), 534-543. https://doi.org/10.1016/j.biopsych.2018.09.025