NR1 knockdown mice as a representative model of the glutamate hypothesis of schizophrenia

N-methyl d-aspartate (NMDA) receptor subunit NR1 knockdown (NR1-KD) mice have a global reduction of NMDA receptors, enabling their use as a genetic model to study the role of NMDA receptors in the pathophysiology of schizophrenia. This targeted mutation results in a spectrum of altered behaviors that are similar to those induced by NMDA receptor antagonists, which have long been used to model schizophrenia in animals. NR1-KD mice serve as a complementary tool to pharmacological models, providing insight into the consequences of sustained NMDA receptor dysfunction in early brain development and throughout the life of the animal. Though in many respects the phenotype of NR1-KD mice mimics that of acute NMDA receptor antagonism, there are also notable differences. In this chapter we highlight some of the molecular, behavioral, and neurophysiological phenotypes of NR1-KD mice and compare these to pharmacological models of NMDA receptor dysfunction. Through the study of these models, our improved understanding of how the brain adapts to persistent NMDA receptor hypofunction may eventually suggest new therapeutic strategies for schizophrenia.