Whole brain transcriptome analysis of Shank2 knock-out mice

Autism spectrum disorders (ASDs) are thought to 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. Here, we show that early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like phenotypes in adult mice. Shank2–/– mice, known to display N-methyl-D-aspartate 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 is rapidly shifted to NMDAR hypofunction after weaning (~P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7?21) prevents the NMDAR hypofunction and autistic-like behaviors from manifesting at later stages (~P28 and P56). These results suggest that early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like behaviors in Shank2–/– mice, and that early correction of NMDAR function has the long-lasting effect of preventing autistic-like phenotypes from developing at later stages. Whole brain transcriptome of 6 P14 WT naïve, 6 P25 WT naïve, 6 P14 Shank2 knock-out naïve, 6 P25 Shank2 knock-out naïve mice.