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Tumor suppressor p53 modulates activity-dependent synapse strengthening, autism-like behavior and hippocampus-dependent learning

Molecular Psychiatry volume 28, pages 3782–3794 (2023)Cite this article

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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.

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Fig. 1: p53 protein expression is induced by cLTP.
Fig. 2: Knocking down p53 impairs cLTP-induced surface expression of AMPAR and strengthening of synapses.
Fig. 3: Knocking down p53 does not alter locomotor activity or anxiety-like behavior in mice.
Fig. 4: Knocking down p53 increases repetitive behavior and reduces sociability in mice.
Fig. 5: Knocking down p53 impairs hippocampus-dependent learning and memory particularly in male mice.
Fig. 6: RNAseq reveals p53-associated genes potentially involved in synaptic plasticity, learning and memory.

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Data availability

The RNA sequencing results can be found at https://doi.org/10.6084/m9.figshare.23560812.v1.

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Acknowledgements

This work is supported by National Institute of Health R01NS105615, R01MH124827 and R21MH122840 to N-P.T.

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Authors and Affiliations

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

    Kwan Young Lee, Yeeun Yook, Catherine A. Christian-Hinman & Nien-Pei Tsai

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

    Haohan Wang

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

    Justin S. Rhodes, Catherine A. Christian-Hinman & Nien-Pei Tsai

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

    Justin S. Rhodes, Catherine A. Christian-Hinman & Nien-Pei Tsai

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

    Justin S. Rhodes

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KYL and NPT designed the research. KYL, HW and YY performed the research and analyzed the data. CAC-H and JSR provided essential instrumental support. KYL and NPT wrote the manuscript.

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Correspondence to Kwan Young Lee or Nien-Pei Tsai.

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Lee, K.Y., Wang, H., Yook, Y. et al. Tumor suppressor p53 modulates activity-dependent synapse strengthening, autism-like behavior and hippocampus-dependent learning. Mol Psychiatry 28, 3782–3794 (2023). https://doi.org/10.1038/s41380-023-02268-9

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