Project Summary/Abstract The process of long-term potentiation (LTP), particularly at the hippocampal Schaffer collateral pathway, has been regarded as one of the most relevant cellular processes underlying learning and memory. Numerous studies have demonstrated that changes in gene transcription are required during the execution of LTP. However, it is much less understood regarding how the dysregulation of gene transcription contributes to intellectual disability and what transcription factors are involved. To approach this question, we gathered preliminary data to show an elevation of tumor suppressor p53 following the induction of N-methyl-D-aspartate receptor (NMDAR)- dependent LTP. It has been well-established that LTP requires elevated surface expression of α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR). Our data showed that knocking down p53 in forebrain excitatory neurons diminished the surface expression of AMPAR during LTP and ultimately impaired learning and memory behavior in mice in vivo. Importantly, we also observed abnormally down-regulated p53 in two mouse models of intellectual disability. We therefore propose to test the hypothesis that p53-dependent transcription is required for activity-dependent synaptic plasticity, learning, and memory, and its dysregulation is associated with intellectual disability. In Aim 1, we propose to characterize how p53-dependent gene transcription mediates AMPAR surface expression and participates in hippocampal LTP. In Aim 2, we will employ genetic and pharmacological approaches to restore p53 in two mouse models of intellectual disability with the intent to improve hippocampal synaptic plasticity and learning behavior. We expect our work to facilitate a much deeper understanding of hippocampal synaptic plasticity and open new avenues for the study and potential correction of neurological and psychiatric disorders that are associated with intellectual disability.