The structural modification of dendritic spines on neurons, which includes growth and shrinkage, is an important process for memory formation. Both types of structural changes are mediated by the activation of proteins called NMDARs that are present on the spines. Schizophrenia is a psychiatric disorder associated with spine loss and reduced levels of d-serine. As simultaneous binding of endogenous chemicals, glutamate and d-serine, to NMDARs is required for spine growth, but the binding of glutamate alone instead results in spine shrinkage in a process called non-ionotropic NMDAR signaling, our lab hypothesized that lowered d-serine levels associated with schizophrenia enhances non-ionotropic NMDAR signaling to promote shrinkage and loss of spines instead of growth. Using a mouse model of schizophrenia that cannot produce d-serine, our results indeed demonstrate a bias for spine shrinkage over growth. Our research supports a model of novel molecular mechanism of schizophrenia that lowered d-serine levels enhances non-ionotropic NMDAR signaling to promote spine shrinkage that could play a role in spine loss observed with the disorder.