Early correction of NMDAR function improves autistic-like social behaviors in adult Shank2−/− mice

Background: Autism spectrum disorders (ASD) involve neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many ASD-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 ASD (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see if early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages, and 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-Daspartate receptor (NMDAR) hypofunction and autistic-like behaviors at post-weaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype—NMDAR hyperfunction—at an earlier pre-weaning 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 (P7-21) 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 autisticlike 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.