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 a-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.