The instant invention is based, at least in part, on a newly-identified
proteasome-independent signaling function of ubiquitinated PSD-95. Mdm2 inhibitors, Mdm4 inhibitors, PSD-95 inhibitors, and / or enantiomers and / or derivatives thereof de-crease
endocytosis via preventing PSD-95 ubiquitination, and thereby increase AMPAR, NMDAR, D1
dopamine receptor surface expression in response to a given stimulus (e.g., NMDA, Aβ). Accordingly, the invention provides methods for modulating AM-PARS, NMDARs, or D1
dopamine receptors in a neuronal
cell by contacting the neuronal
cell with an Mdm2 and / or Mdm4 inhibitor or PSD-95 inhibitor and / or enantiomers and / or derivatives thereof. Mdm2 and / or Mdm4 inhibitors decrease the enzymatic activity of the respective proteins, and / or interactions with their respective substrates. Mdm2 and Mdm4 inhibitors and / or PSD-95 inhibitors of the invention are contemplated for use in the treatment of neurological disorders, neurodevelopmental disorders, and psychiatric disorders. The invention also provides methods to screen for new Mdm2 and Mdm4 inhibitors and PSD-95 inhibitors and / or enantiomers and / or derivatives thereof.