Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
School of Information Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Mol Psychiatry. 2023 Sep;28(9):3782-3794. doi: 10.1038/s41380-023-02268-9. Epub 2023 Sep 28.
Synaptic potentiation underlies various forms of behavior and depends on modulation by multiple activity-dependent transcription factors to coordinate the expression of genes necessary for sustaining synaptic transmission. Our current study identified the tumor suppressor p53 as a novel transcription factor involved in this process. We first revealed that p53 could be elevated upon chemically induced long-term potentiation (cLTP) in cultured primary neurons. By knocking down p53 in neurons, we further showed that p53 is required for cLTP-induced elevation of surface GluA1 and GluA2 subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Because LTP is one of the principal plasticity mechanisms underlying behaviors, we employed forebrain-specific knockdown of p53 to evaluate the role of p53 in behavior. Our results showed that, while knocking down p53 in mice does not alter locomotion or anxiety-like behavior, it significantly promotes repetitive behavior and reduces sociability in mice of both sexes. In addition, knocking down p53 also impairs hippocampal LTP and hippocampus-dependent learning and memory. Most importantly, these learning-associated defects are more pronounced in male mice than in female mice, suggesting a sex-specific role of p53 in these behaviors. Using RNA sequencing (RNAseq) to identify p53-associated genes in the hippocampus, we showed that knocking down p53 up- or down-regulates multiple genes with known functions in synaptic plasticity and neurodevelopment. Altogether, our study suggests p53 as an activity-dependent transcription factor that mediates the surface expression of AMPAR, permits hippocampal synaptic plasticity, represses autism-like behavior, and promotes hippocampus-dependent learning and memory.
突触强化是各种形式的行为的基础，依赖于多种活性依赖性转录因子的调节，以协调维持突触传递所需的基因的表达。我们目前的研究确定肿瘤抑制因子 p53 是参与该过程的新型转录因子。我们首先揭示了在培养的原代神经元中，化学诱导的长时程增强（cLTP）可使 p53 升高。通过在神经元中敲低 p53，我们进一步表明 p53 对于 cLTP 诱导的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的表面 GluA1 和 GluA2 亚基的升高是必需的。因为 LTP 是行为的主要可塑性机制之一，所以我们采用大脑前部特异性敲低 p53 来评估 p53 在行为中的作用。我们的结果表明，虽然在小鼠中敲低 p53 不会改变运动或焦虑样行为，但它显著促进了重复性行为，并降低了两性小鼠的社交能力。此外，敲低 p53 还损害了海马体的 LTP 和海马体依赖性学习和记忆。最重要的是，这些与学习相关的缺陷在雄性小鼠中比在雌性小鼠中更为明显，这表明 p53 在这些行为中具有性别特异性作用。通过使用 RNA 测序（RNAseq）来鉴定海马体中与 p53 相关的基因，我们表明敲低 p53 上调或下调了具有已知在突触可塑性和神经发育中作用的多个基因。总之，我们的研究表明 p53 是一种活性依赖性转录因子，可介导 AMPAR 的表面表达，允许海马体的突触可塑性，抑制自闭症样行为，并促进海马体依赖性学习和记忆。
