Waisman Center, University of Wisconsin-Madison, Madison, WI, 53705, USA.
Department of Animal Sciences, College of Agriculture and Life Sciences, University of Wisconsin-Madison, Madison, WI, 53705, USA.
BMC Med. 2022 May 13;20(1):163. doi: 10.1186/s12916-022-02370-9.
Fragile X syndrome (FXS), the most prevalent inherited intellectual disability and one of the most common monogenic forms of autism, is caused by a loss of fragile X messenger ribonucleoprotein 1 (FMR1). We have previously shown that FMR1 represses the levels and activities of ubiquitin ligase MDM2 in young adult FMR1-deficient mice, and treatment by a MDM2 inhibitor Nutlin-3 rescues both hippocampal neurogenic and cognitive deficits in FMR1-deficient mice when analyzed shortly after the administration. However, it is unknown whether Nutlin-3 treatment can have long-lasting therapeutic effects.
We treated 2-month-old young adult FMR1-deficient mice with Nutlin-3 for 10 days and then assessed the persistent effect of Nutlin-3 on both cognitive functions and adult neurogenesis when mice were 6-month-old mature adults. To investigate the mechanisms underlying the persistent effects of Nutlin-3, we analyzed the proliferation and differentiation of neural stem/progenitor cells isolated from these mice and assessed the transcriptome of the hippocampal tissues of treated mice.
We found that transient treatment with Nutlin-3 of 2-month-old young adult FMR1-deficient mice prevents the emergence of neurogenic and cognitive deficits in mature adult FXS mice at 6 months of age. We further found that the long-lasting restoration of neurogenesis and cognitive function might not be mediated by changing intrinsic properties of adult neural stem cells. Transcriptomic analysis of the hippocampal tissue demonstrated that transient Nultin-3 treatment leads to significant expression changes in genes related to the extracellular matrix, secreted factors, and cell membrane proteins in the FMR1-deficient hippocampus.
Our data indicates that transient Nutlin-3 treatment in young adults leads to long-lasting neurogenic and behavioral changes likely through modulating adult neurogenic niche that impact adult neural stem cells. Our results demonstrate that cognitive impairments in FXS may be prevented by an early intervention through Nutlin-3 treatment.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍之一，也是最常见的单基因形式的自闭症之一，由脆性 X 信使核糖核蛋白 1（FMR1）缺失引起。我们之前已经表明，FMR1 抑制年轻成年 FMR1 缺陷型小鼠中泛素连接酶 MDM2 的水平和活性，并且当在给药后不久分析时，MDM2 抑制剂 Nutlin-3 的治疗可挽救 FMR1 缺陷型小鼠的海马神经发生和认知缺陷。然而，尚不清楚 Nutlin-3 治疗是否具有持久的治疗效果。
我们用 Nutlin-3 治疗 2 个月大的年轻成年 FMR1 缺陷型小鼠 10 天，然后在 6 个月大的成熟成年时评估 Nutlin-3 对认知功能和成年神经发生的持久影响。为了研究 Nutlin-3 持久作用的机制，我们分析了从这些小鼠分离的神经干细胞/祖细胞的增殖和分化，并评估了治疗小鼠海马组织的转录组。
我们发现，短暂用 Nutlin-3 治疗 2 个月大的年轻成年 FMR1 缺陷型小鼠可预防 6 个月大的 FXS 成熟成年小鼠出现神经发生和认知缺陷。我们进一步发现，神经发生和认知功能的持久恢复可能不是通过改变成年神经干细胞的内在特性来介导的。海马组织的转录组分析表明，短暂的 Nutlin-3 处理导致与 FMR1 缺陷型海马体中的细胞外基质、分泌因子和细胞膜蛋白相关的基因表达发生显著变化。
我们的数据表明，年轻成年时的短暂 Nutlin-3 治疗可能通过调节影响成年神经干细胞的成年神经发生小生境导致持久的神经发生和行为变化。我们的结果表明，通过 Nutlin-3 治疗的早期干预，可预防 FXS 的认知障碍。
