Summary: Scientists have discovered a direct link between the protein p53 and autism-like behavior in mice. The researchers studied the effects of manipulating p53 levels in the mouse hippocampus.
Reduced levels resulted in repetitive behavior, diminished sociability, and impaired learning, especially in male mice. This pivotal work uncovers the intricate role of p53 in neurodevelopmental disorders like autism.
Lowered hippocampal p53 levels in mice led to repetitive behavior, decreased sociability, and hindered hippocampus-dependent learning.
Elevated p53 levels were observed during periods of enhanced communication between hippocampal neurons, related to positive learning outcomes.
Previous research from 2018 identified p53’s significant role in irregular brain cell activity seen in both ASD and epilepsy.
Source: Beckman Institute
Researchers have established the protein p53 as critical for regulating sociability, repetitive behavior, and hippocampus-related learning and memory in mice, illuminating the relationship between the protein-coding gene TP53 and neurodevelopmental and psychiatric disorders like autism spectrum disorder.
“This study shows for the first time that p53 is linked directly to autism-like behavior,” said Nien-Pei Tsai, an associate professor of molecular and integrative biology at the University of Illinois Urbana-Champaign and a researcher at the Beckman Institute for Advanced Science and Technology.
In living systems, genes act as a biological version of binary code, using the letters A, C, G, and T instead of ones and zeroes to spell out cellular marching orders. Some genes — called coding genes — instruct cells to create proteins with specific functions. For example, the gene TP53 instructs cells to create the protein p53; its job is to regulate how other genes are expressed.
In this study, Tsai and his colleagues lowered hippocampal p53 levels in mice, looking for changes in gene expressions related to behavior. They observed that the decreased p53 levels:
Promoted repetitive behavior in mice.
Reduced sociability in mice.
Impaired hippocampus-dependent learning and memory, especially in male mice.
The researchers also observed that p53 levels were elevated after a period of active communication between hippocampal neurons called long-term potentiation. Flexible neuron firing — known as plasticity — is related to positive learning and memory outcomes.
In a 2018 study, Tsai and his colleagues identified p53 as a key protein involved in the irregular brain cell activity seen in ASD and epilepsy. In future studies, they aim to explore how p53 coordinates the expression of those autism-linked genes to guide behavior.
The paper associated with this study is titled “Tumor suppressor p53 modulates activity-dependent synapse strengthening, autism-like behavior and hippocampus-dependent learning” and appears in the journal Molecular Psychiatry.
Funding: Research reported in this press release was supported by the National Institutes of Health under award numbers R01NS105615, R01MH124827, and R21MH122840. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
About this genetics, ASD, and memory research news
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.