Figure 7.

Working model of p53 and Nedd4-2 in FMRP-dependent homeostatic synaptic downscaling. In WT neurons, chronic activity stimulation triggers the Akt-Mdm2 pathway and leads to p53 down-regulation. A feedforward mechanism subsequently stabilizes Akt and promotes Nedd4-2 phosphorylation and the interaction between Nedd4-2 and 14-3-3. In Fmr1 KO neurons, chronic activity stimulation fails to further elevate Mdm2 phosphorylation or trigger p53 down-regulation. Destabilized Akt leads to Nedd4-2 dephosphorylation and occludes GluA1 ubiquitination even in the presence of 14-3-3. Although Mdm2 is basally phosphorylated in Fmr1 KO neurons, it is predicted that a compensatory mechanism is maintaining p53 level or an inhibitory molecule is interfering with Mdm2-p53 interaction in Fmr1 KO neurons.