Elsevier

Biological Psychiatry

Volume 85, Issue 7, 1 April 2019, Pages 534-543
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2018.09.025Get rights and content

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.

Section snippets

Animals

Shank2−/− mice lacking the exons 6 and 7 of the Shank2 gene have been previously reported (38). Shank2−/− mice lacking exon 7 (37) and exon 24 (33) have also been previously reported. All mutant and their wild-type (WT) littermates of Shank2−/− mice lacking exons 6 and 7 were generated on and backcrossed to a C57BL/6N background for >20 generations. Shank2−/− mice lacking exons 6 and 7 under a different background (C57BL/6J) were generated by backcrossing the original mice in the genetic

Distinct Transcriptomic Profiles in Shank2−/− Mouse Brains at P14 and P25

Mice lacking SHANK2/PROSAP1 (Shank2−/− mice; exons 6 and 7; global deletion) display autistic-like social deficits that are rapidly improved by acute D-cycloserine (NMDAR agonist) treatment at juvenile and adult stages (38). However, excitatory synaptogenesis in mice is most active during the first 3 postnatal weeks (46), and expression levels of SHANK2 protein in the whole brain peak at ∼P14 (Figure 1A), although SHANK2 messenger RNA levels did not show a similar pattern (Figure 1B).

We thus

Discussion

Our study provides early NMDAR hyperfunction at ∼P14 as a causal mechanism for the NMDAR hypofunction and social deficits in Shank2−/− mice at juvenile (∼P28) and adult (∼P56) stages. In support of this, Shank2−/− mice display a rapid reversal of NMDAR function during P14 and P21 in the hippocampus (Figure 2, Supplemental Figures S3–S5) as well as in the mPFC (Supplemental Figures S6 and S7). Importantly, early memantine treatment (P7–P21) normalizes NMDAR function and social interaction

Acknowledgments and Disclosures

This work was supported by the National Research Foundation (NRF) (Grant No. NRF-2013M3C7A1056732 [to HyuKi]), NRF-2013-Fostering Core Leaders of the Future Basic Science Program (Grant No. NRF-2013H1A8A1004150 [to CC]), Global Ph.D. Fellowship Program (Grant No. NRF-2013H1A2A1032785 [to SH] and Grant No. NRF-2015H1A2A1033937 [to RK]), the National Honor Scientist Program (Grant No. NRF-2012R1A3A1050385 [to B-KK]), the National Institute of Health grants (Grant Nos. MH098114, MH104316, and

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    WM and HW are currently affiliated with the Department of Genetics and University of North Carolina Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina. C-SL is currently affiliated with the Department of Pharmacology, Wonkwang University School of Medicine, Iksan, South Korea.

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    CC and SH contributed equally to this work.

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