이관영 (University of Illinois at Urbana-Champaign)

한빛사논문

조회279

University of Illinois at Urbana-Champaign

CV File 168 kb

Mol. Psychiatr., Sep 28 2023, | https://doi.org/10.1038/s41380-023-02268-9 Tumor suppressor p53 modulates activity-dependent synapse strengthening, autism-like behavior and hippocampus-dependent learning.

Kwan Young Lee¹, Haohan Wang², Yeeun Yook¹, Justin S. Rhodes^3,4,5, Catherine A. Christian-Hinman^1,3,4 and Nien-Pei Tsai ^1,3,4

¹Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

²School of Information Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

³Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

⁴Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

⁵Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA.

Corresponding authors : Correspondence to Kwan Young Lee or Nien-Pei Tsai.

Abstract

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.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-10-11)
연구진국외 연구진
분야 생명과학 > 생리학

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