Distinct NMDA receptor signaling domains regulate hippocampal network dynamics

PROJECT SUMMARY/ABSTRACT Schizophrenia is characterized by discordant thought processes, perceptions, emotional responsiveness, and social interactions impacting up to 0.7 % of the US population (National Institute of Mental Health, Health Statistics). While rates of occurrence are low, schizophrenia ranks in the top fifteen leading causes of work disability worldwide due to the severity of the symptoms. First episodes of schizophrenia typically occur in the late adolescence to early adulthood. It is believed that interactions between genetic factors and aversive early life experiences lead to abnormal brain development which produces the schizophrenia symptoms. While widespread changes in the brains of schizophrenic patients have been documented, it is thought that the cognitive disorganization relies on pathological processes within the hippocampus. As evidence, aberrant network oscillations in the hippocampus in association with a selective spatial memory deficit are prominent in schizophrenic patients. Within the N-methyl-D-aspartate receptor (NMDAR) hypofunction model of schizophrenia, GluN2B subnits have been implicated in changes in theta and slow gamma oscillations, cross frequency couping, and impaired spatial memory. However, this situation is made more complex by the fact that GluN2 subunits regulate ionotropic and direct intracellular signaling and these factors have not been addressed fully with respect to the regulation of network oscillations and memory retrieval. We created transgenic mice expressing chimeric GluN2 subunits in the forebrain to separate the ionotropic and direct intracellular signaling processes downstream from NMDAR activation and discovered that heightened GluN2B- type intracellular signaling enhances long-term spatial, but not non-spatial memory performance. Since slow gamma oscillations in the hippocampus provide the functional network organization for spatial memory retrieval, it is possible that GluN2B-type intracellular signaling regulates slow gamma oscillations to mediate its effects on long-term spatial memory. We propose that inappropriate GluN2B-type CTD signaling is a critical factor in the alterations in slow gamma oscillations and spatial memory in schizophrenia. We will test this idea and extend the question to specific synapses by analyzing theta and slow gamma oscillations, cross frequency coupling, and spatial memory performance in transgenic mice expressing chimeric GluN2 subunits in the forebrain or limited to hippocampal principal cells or parvalbumin-positive interneurons. We predict that heightened GluN2B-type CTD signaling at excitatory synapses onto principal cells or interneurons will accentuate slow gamma function during planning of paths to know goal locations and improve spatial memory. These findings would support GluN2B-type CTD signaling as a powerful factor in the regulation of hippocampal network dynamics and spatial memory. Outcomes from this study will transform our understanding of the neurobiological bases of schizophrenia and provide a novel framework for future research.