Objective To investigate the effects of specific knockout of the Mecp2 gene in dentate gyrus (DG) neurons on adult hippocampal neurogenesis (AHN) and autism spectrum disorder (ASD)-like behaviors in mice, so as to provide potential therapeutic directions for ASD caused by genetic abnormalities. Methods Mecp2-flox mice were randomly divided into four groups: Mecp2f/y, Mecp2f/y-Con, wild-type (WT), and WT-Con groups,with 6 mice in each group. Western Blot was used to determine the protein expression levels of MeCP2 and brain-derived neurotrophic factor (BDNF).ASD-like behaviors were evaluated using the three-chamber sociability test, novel object recognition (NOR) test, Y-maze, Morris water maze (MWM), open field test, marble burying test, and self-grooming test. Immunofluorescence staining was utilized to assess hippocampal neurogenesis. Results Compared withMecp2f/y-Con group and WT group, Mecp2f/y mice exhibited significantly decreased sociability and social novelty indices (P<0.05), impaired cognitive performance indicated by a reduced recognition index in the NOR test (P<0.001), decreased duration and entries into the novel arm of the Y-maze (P<0.05),shortened target quatrant dwell time (P<0.05) and fewer platform crossings in the Morris water maze (P<0.05), reduced center dwell time in the open field test (P<0.05), and increased marble burying count, as well as elevated frequency and duration of self-grooming (P<0.05). Furthermore, significant reductions were observed in the number of Nestin+,Nestin+MCM2+,Tbr2+,Tbr2+MCM2+,DCX+,DCX+MCM2+ and BrdU+NeuN+ cells (P<0.05), while the number of BrdU+DCX+ immature neurons was significantly increased (P<0.01). The protein expression level of BDNF was significantly decreased in Mecp2f/y mice(P<0.05). Conclusion The specific knockout of the Mecp2 gene in mouse DG neurons disrupts AHN, and consequently induces ASD-like behaviors, which provide experimental evidence for the neurobiological mechanisms underlying ASD.
Key words
Mecp2 gene /
autism spectrum disorder-like behaviors /
dentate gyrus /
adult hippocampal neurogenesis /
brain-derived neurotrophic factor
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