"Neural Adaptations to Sustained NMDA Receptor Hypofunction"

The NMDA receptor (NMDAR) plays an important role in forming proper neural connections during development and in shaping connections with experience. Because these processes are fundamental to neuron biology, a number of disease states can occur when NMDARs are over- or underactive. Specifically, some forms of schizophrenia and autism are believed to result from NMDAR hypofunction. We have used a genetic model with reduced levels of NMDARs to model schizophrenia in mice and to understand the molecular and cellular changes that occur in the brain as a consequence of NMDAR hypofunction. Our work has focused on the resultant impairments in dopamine neurotransmission, since this is the target of currently prescribed antipsychotics. We have discovered that, in contrast to acute NMDAR antagonism, sustained NMDAR hypofunction leads to a dramatic remodeling of dopamine neuron biology at several key points of homeostasis. As a result of these changes, dopamine neurons are incapable of generating dopamine surges that the brain uses to encode significance to environmental stimuli. The seminar will detail these findings, as well as the implications for our understanding of psychosis and our interpretation of clinical postmortem studies.