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Biol Psychiatry. 2019 Apr 1;85(7):534-543. doi: 10.1016/j.biopsych.2018.09.025. Epub 2018 Oct 9.

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

Author information

1
Department of Biological Sciences, South Korea; Center for Synaptic Brain Dysfunctions, Institute for Basic Science, South Korea.
2
Department of Biological Sciences, South Korea.
3
Department of Convergence Technology Research, Korea Institute of Science and Technology Information, Daejeon, South Korea.
4
Center for Synaptic Brain Dysfunctions, Institute for Basic Science, South Korea.
5
Department of Pediatrics, Duke University, Durham, North Carolina.
6
Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, South Korea.
7
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
8
Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul, South Korea.
9
School of Biological Sciences, Seoul National University, Seoul, South Korea.
10
Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.
11
Department of Mathematical Sciences, Korea Advanced Institute for Science and Technology, South Korea.
12
Department of Pediatrics, Duke University, Durham, North Carolina; Department of Neurobiology, Duke University, Durham, North Carolina; Cell and Molecular Biology Program, Duke University, Durham, North Carolina; Duke Institute of Brain Science, Duke University, Durham, North Carolina; Genomics and Genetics Program, Duke University, Durham, North Carolina.
13
Department of Biological Sciences, South Korea; Center for Synaptic Brain Dysfunctions, Institute for Basic Science, South Korea. Electronic address: kime@kaist.ac.kr.

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.

KEYWORDS:

Autism; Memantine; NMDA receptor; SHANK2; Synapse; Treatment

PMID:
30466882
PMCID:
PMC6420362
[Available on 2020-04-01]
DOI:
10.1016/j.biopsych.2018.09.025
[Indexed for MEDLINE]

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