Priority CommunicationEarly Correction of N-Methyl-D-Aspartate Receptor Function Improves Autistic-like Social Behaviors in Adult Shank2−/− Mice
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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2022, Biological PsychiatryCitation Excerpt :Shank2 mutant mice show NMDAR hyperfunction at ∼P14, which contrasts with NMDAR hypofunction seen at ∼P25 (74). Normalizing NMDAR hyperactivity by early chronic (P7–21) memantine (NMDAR antagonist) treatment prevents NMDAR hypoactivity and behavioral deficits at ∼P25 and ∼P56 (74). Mice haploinsufficient for Grin2b (encoding the NMDAR GluN2B subunit), or with a patient-derived mutation (GluN2B-C456Y), show NMDAR hypofunction at ∼P21 and anxiolytic-like behavior at >P56 (75).
Dysfunctional D-aspartate metabolism in BTBR mouse model of idiopathic autism
2020, Biochimica et Biophysica Acta - Proteins and ProteomicsCitation Excerpt :It is important to remark that our neurochemical analyses were conducted in adult animals while ASD mainly involves neurodevelopmental dysfunctions that result in clear phenotypes at juvenile stages of life. Remarkably, such juvenile phenotypes differ from those at adulthood at the molecular level [89]. Studies have now established that ASD is associated, at least in animal models, to early hyperfunction of NMDAR before weaning while switching to hypofunction after this period [89].
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.