Whole brain transcriptome analysis of Shank2 knock-out mice. Mus musculus

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. Overall design: 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.

自闭症谱系障碍（Autism Spectrum Disorders, ASDs）被认为与神经发育失调密切相关，此类失调会在生命早期引发可见的临床症状。诸多由动物实验提出的ASD相关致病机制，已通过“对失调机制进行实验性逆转后，成年动物的类自闭症表型得到显著改善”这一结果得到验证。然而，此类机制是否同样在生命早期发挥作用，从而引发类自闭症表型，目前尚不明确。本研究证实，对幼年小鼠体内的失调机制进行早期干预矫正，可阻止成年小鼠出现类自闭症表型。已知Shank2基因敲除（Shank2–/–）小鼠在出生后第21天（P21）后的断乳后阶段，会表现出N-甲基-D-天冬氨酸受体（N-methyl-D-aspartate receptor, NMDAR）功能低下与类自闭症行为；但在更早的断乳前阶段（约P14），该类小鼠却呈现出与之相反的突触表型——NMDAR功能亢进。此外，该类小鼠在P14时的NMDAR功能亢进，会在断乳后（约P24）快速转变为NMDAR功能低下。通过NMDAR拮抗剂美金刚（于出生后第7天至第21天给药）对早期NMDAR功能亢进进行慢性抑制，可阻止该类小鼠在后续阶段（约P28与P56）出现NMDAR功能低下与类自闭症行为。上述结果表明，在Shank2–/–小鼠中，早期的NMDAR功能亢进会导致后期出现NMDAR功能低下与类自闭症行为；而早期矫正NMDAR功能，可产生长效作用，阻止类自闭症表型在后续阶段出现。实验设计：针对6只P14未干预野生型小鼠、6只P25未干预野生型小鼠、6只P14未干预Shank2基因敲除小鼠、6只P25未干预Shank2基因敲除小鼠的全脑转录组开展分析。