D-serine is a selective endogenous activator of the NMDAR D-serine/glycine site that is involved in abnormal glutamate transmission in schizophrenia. The enzyme serine racemase (SR) directly converts L- serine to D-serine and is present in astrocytes and neurons. Our pilot studies indicated that Disrupted-In- Schizophrenia-1 (DISC1) binds to SR and regulate D-serine production by astrocytes. We hypothesize that abnormal DISC1-SR interaction will affect D-serine metabolism, leading to abnormal glutamatergic neurotransmission and resultant schizophrenia-relevant behaviors. Specific Aim 1 will determine the mechanisms of DISC1-SR interaction. We will map binding domains for both proteins and compare binding of SR to DISC1 in astrocytes vs. neurons. Specific Aim 2 will determine the role of DISC1 in the regulation of D-serine production. We will elucidate how changes in DISC1 affect levels of SR and D-serine metabolism in neurons vs. astrocytes. Specific Aim 3 will evaluate the role of DISC1-SR interaction in glutamatergic synaptic transmission in the cortex and hippocampus. We will determine whether expression of mutant DISC1 in astrocytes vs. neurons alters different parameters of glutamatergic synaptic transmission. Specific Aim 4 will identify the effects of SR-DISC1 interaction on schizophrenia-like behaviors. We will probe schizophrenia-related behaviors in transgenic mice and determine whether these phenotypic changes can be rescued with D-serine and/or D-cycloserine. The grant application will uncover the molecular mechanisms whereby DISC1 interacts with SR to regulate D-serine production and influences glutamate neurotransmission and schizophrenia-like behaviors. PUBLIC HEALTH RELEVANCE: The grant application proposes to determine the molecular mechanisms whereby a mutant human gene, Disrupted-In-Schizophrenia 1 (DISC1), associated with schizophrenia and related psychiatric disorders, affects metabolism of D-serine, a critical molecule, involved in glutamate neurotransmission known to be altered in schizophrenia. The proposal will advance our understanding of the pathogenic mechanisms of serious psychiatric diseases and will facilitate use of this new model for pre-clinical therapeutic trials.