Protein-protein interaction–interfering peptide rescues dysregulated NMDA receptor signaling

The complex and heterogeneous genetic architecture of neuropsychiatric illnesses compels us to look beyond individual risk genes for therapeutic strategies and target the interactive dynamics and convergence of their protein products. A mechanistic substrate for convergence of synaptic neuropsychiatric risk genes are protein-protein interactions (PPIs) in the N-methyl-D-aspartate receptor (NMDAR) complex. NMDAR hypofunction in schizophrenia is associated with hypoactivity of Src kinase, resulting from convergent alterations in PPIs of Src with its partners. Of these, the association of Src with PSD-95, which inhibits the activity of this kinase in the NMDAR complex, is known to be increased in schizophrenia. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 by employing a cell-penetrating and Src-activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP enhanced synaptic NMDAR currents in Src+/- and Sdy-/- mice manifesting NMDAR hypofunction phenotypes. Chronic intracerebroventricularly (ICV) injection of TAT-SAPIP rescued cognitive deficits in trace fear conditioning in Src +/- mice. Moreover, TAT-SAPIP enhanced Src activity in synaptoneurosomes derived from dorsolateral prefrontal cortex of 14 patients. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.