Abstract
D-Serine, an endogenous coagonist of N-methyl-d-aspartate receptors (NMDARs) at the glycine binding site, is synthesized by serine racemase (SR) through conversion of l-Serine. Dysregulation of SR/D-Serine and Disrupted-In-Schizophrenia-1 (DISC1) contributes to the pathogenesis of schizophrenia at converging pathways, as perturbation of SR-DISC1 binding in astrocytes elicits schizophrenia-like behaviors in mice. However, an association of neuronal SR with DISC1 remains elusive. Here we report that SR associates with DISC1 and its agglomerates in cortical neurons, which can be modulated by NMDAR activity. Endogenous SR colocalizes with DISC1 large agglomerates in the soma and with smaller puncta in the nucleus and dendrites of cortical neurons. Co-immunoprecipitation assays demonstrate SR interaction with DISC1 in cortical neuronal lysates, suggesting the physiological presence of functional SR-DISC1 complexes in neurons. Moreover, exogenous d-Serine application significantly increases the interaction of SR with DISC1, the number of DISC1-SR large agglomerates and the levels of DISC1 agglomerated form along with SR in the triton-insoluble pellet fraction, whereas application of glycine with a glycine transporter inhibitor fails to increase their interactions, abundance of DISC1-SR large agglomerates and levels of DISC1 agglomerated form. This increase by d-Serine application is blocked by 7-chlorokynurenic acid, a specific antagonist at the glycine site of NMDARs, suggesting mediation through NMDARs. Our findings thus demonstrate neuronal SR association with DISC1 and its agglomerates, which can be modulated by d-Serine, thereby validating a novel neuronal SR-DISC1 complex responsive to NMDAR activation and providing a molecular mechanism by which pathways implicated in schizophrenia converge.