Blocking Src-PSD-95 interaction rescues glutamatergic signaling dysregulation in schizophrenia.
The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employingacell penetrating andSrc activating PSD-95 inhibitory peptide(TAT-SAPIP). TAT-SAPIPselectively increased post-synaptic Src activity in humans and mice, andenhanced synaptic NMDAR currents in mice.Chronic ICV injection ofTAT-SAPIPrescued deficits intrace fear conditioning in Src hypomorphic mice.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.