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

Scientists studied a protein called p53 in mouse brains and found it plays an important role in how brain cells communicate. When they reduced p53 levels, mice showed autism-like behaviors including repetitive actions and reduced social interest. The mice also had trouble with learning and memory. These effects were stronger in male mice than female mice, which may help explain why autism affects more boys than girls.

This preclinical study investigated the role of tumor suppressor protein p53 in synaptic plasticity and autism-related behaviors. Researchers found that p53 is elevated during long-term potentiation and is required for proper AMPA receptor function. When p53 was knocked down in mouse forebrains, it resulted in increased repetitive behaviors, reduced sociability, and impaired hippocampal learning and memory. These effects were more pronounced in males than females, suggesting sex-specific mechanisms.

RNA sequencing revealed that p53 regulates multiple genes involved in synaptic plasticity and neurodevelopment. The findings suggest p53 may be an important transcription factor linking synaptic function to autism-like behaviors.

While promising for understanding autism neurobiology, this early-stage research requires human validation before clinical applications. The identification of sex-specific effects and synaptic mechanisms may inform future therapeutic targets, but translation to clinical practice is premature.

This is a preclinical mouse study with unclear sample sizes. The relevance to human autism requires validation. The study does not establish whether p53 dysfunction occurs in human autism or whether targeting this pathway could be therapeutic.

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.