Gm527 deficiency in dentate gyrus improves memory through upregulating dopamine D1 receptor pathway

AIMS: Dopamine D1 receptor (D1R) hypofunction is associated with negative and cognitive symptoms in schizophrenia; therefore, the mechanism of D1R function modulation needs further investigation. Gm527 is the rodent homologous of the schizophrenia‐related gene C14orf28, encoding a predicated D1R‐interacting protein. However, the role of Gm527‐D1R interaction in schizophrenia needs to be clarified. METHODS: Gm527‐floxed mice were generated and crossed with D1‐Cre mice (D1:Gm527−/−) to knockout Gm527 in D1R‐positive neurons. Then behavioral tests were performed to explore the schizophrenia‐related phenotypes. Immunofluorescence, fluorescence in situ hybridization, electrophysiological recording, quantitative real‐time PCR, and western blotting were conducted to investigate the mechanisms. RESULTS: Working memory, long‐term memories, and adult neurogenesis in the DG were enhanced in D1:Gm527−/− mice. LTP was also increased in the DG in D1:Gm527−/− mice, resulting from the Gm527 knockout‐induced D1R expression enhancement on the plasma membrane and subsequently cAMP signaling and NMDA receptor pathways activation. The requirement of Gm527 knockout in the DG was confirmed by reversing Gm527 expression or knockdown Gm527 in the DG D1R‐positive neurons through AAV‐CAG‐FLEX‐Gm527‐GFP or AAV‐CMV‐FLEX‐EGFP‐Gm527‐RNAi injection. CONCLUSIONS: The DG Gm527 knockout induces D1R hyperfunction in improving schizophrenia cognitive symptoms.