Comparison of DEG between memantine-, vehicle-treated and naive Shank2 wild-type and knock-out mice

Autism spectrum disorders (ASDs) are thought to involve diverse 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 play important roles in the development of 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 in Shank2–/– mice by the NMDAR antagonist memantine before weaning (P7–21) prevents the NMDAR hypofunction and autistic-like behaviors from manifesting at later stages (~P28 and P56). In addition, early memantine treatment of Shank2–/– mice substantially alters transcription of numerous genes, driving gene expression patterns in a direction largely opposite that observed in drug-untreated Shank2–/– mice, which, interestingly, mimic those observed in autistic individuals. These results suggest that early NMDAR hyperfunction in Shank2–/– mice leads to late NMDAR hypofunction and autistic-like behaviors, and that early correction of NMDAR function has the long-lasting effect of preventing autistic-like phenotypes from developing at later stages. This SuperSeries is composed of the SubSeries listed below. Whole brain transcriptome of 3 naïve P14, naïve P25, early memantine treated WT and Shank2 knock-out mutant mice in both sex. Refer to individual Series